Richter transformation, usually a diffuse large B-cell lymphoma developing in a person with CLL, remains a challenging entity, but novel regimens look promising, as described at the 2022 Pan Pacific Lymphoma Conference by Matthew S. Davids, MD, MMSc, Associate Professor of Medicine at Harvard Medical School and Director of Clinical Research in the Division of Lymphoma at Dana-Farber Cancer Institute, Boston.1
“As we’ve gotten better at treating CLL, we’ve unfortunately had to deal with Richter transformation,” Dr. Davids said. “With conventional regimens, this condition has a poor prognosis, with median overall survival only 6 to 12 months, but there are some promising future treatment options.”
Who Develops Richter Transformation?
Risk factors associated with Richter transformation (some more strongly than others) include certain germline genotypes, somatic genetic events (especially involving TP53 dysfunction, c-Myc activation, CDKN2A deletion, and trisomy 12 with NOTCH1 mutation), treatment of chronic lymphocytic leukemia (CLL) with purine analogs plus alkylating agents, some clinical factors (bulky lymphadenopathy, Rai stage III–IV), and certain biological characteristics (especially certain stereotyped B-cell receptors or unmutated IGHV VH4-39).
Matthew S. Davids, MD, MMSc
“Historically, we’ve seen the highest rates of Richter transformation in patients who have been through multiple rounds of treatment for CLL,” he said. “Clinically, Richter transformation can be suspected in the patient with CLL who develops rapid clinical deterioration, fever in the absence of infection, rapid and discordant growth of lymph nodes, and/or a sudden and excessive rise in lactate dehydrogenase levels. They are all clues that Richter transformation could be present.”
Incidence and Prognosis
Most published series place the incidence of Richter transformation at 3% to 4%. Prognosis is poor; in large databases, median overall survival has been shown to be 8 months2 to 9.5 months.3 However, in a “real-world analysis” led by Dr. Davids, which included patients previously treated for CLL with targeted agents, median overall survival was only 3.3 months.4
Whether Richter transformation is clonally related to CLL or unrelated influences prognosis. Most cases are clonally related, and such patients have particularly poor outcomes. About 20% of patients have clonally unrelated Richter transformation, and their outcomes are similar to those in de novo diffuse large B-cell lymphoma (DLBCL) “and therefore better,” he noted. In clinical practice, distinguishing between these two entities is challenging. Although there are some prognostic scoring systems, outcomes for most patients are poor, regardless of their scores on these algorithms, Dr. Davids added.
Diagnosis of Richter Transformation
For diagnosis, positron-emission tomography–fluorodeoxyglucose (PET-FDG) avidity alone provides insufficient sensitivity and specificity, and therefore lymph node biopsy guided by PET is mandatory to make the diagnosis. When possible, clonal relationships should be determined to obtain prognostic information.
In patients whose CLL was previously treated only with chemoimmunotherapy, PET plus computed tomography (CT) may help to identify those patients at highest risk for Richter transformation, as indicated by a maximum standardized uptake (SUVmax) value greater than 10. However, it appears less useful in the more modern era of B-cell receptor pathway inhibitors, according to a study of patients with CLL treated with ibrutinib and/or idelalisib.5 In this population, PET/CT SUVmax < 10 vs ≥ 10 had a sensitivity of 71%, a specificity of 50%, and a positive predictive value of 26% in distinguishing Richter transformation from CLL progression. Biopsy was a far more accurate predictor, Dr. Davids commented.
The diagnosis of Richter transformation can be challenging. In a prospective study of patients with CLL receiving standard therapy, 17.5% of cases deemed Richter transformation by community pathologists could not be confirmed by central review.6 “I think this highlights the importance of having expert hematopathologists review these cases to make this diagnosis,” he noted.
Is There a ‘Right’ Management?
Criteria for treatment selection include the following:
- Age, fitness, medical comorbidities: Is the patient a candidate for anthracycline-based chemoimmunotherapy?
- Prior treatment of CLL: Has the patient undergone previous treatment or not?
- CLL genetics: What is the patient’s TP53 status and clonal relatedness (if known)?
- Availability of clinical trials: Is the patient a candidate?
The current approach is usually chemoimmunotherapy. Treatment is based on regimens traditionally used for de novo DLBCL, but outcomes are usually worse than for similarly treated DLBCL. For most patients, the recommended regimens are R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), or R-DA-EPOCH (rituximab and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin). Complete responses are seen in about 5% to 20% of patients and are typically short-lived. Median progression-free survival and overall survival are in the range of 6 and 12 months, respectively.
Hematopoietic stem cell transplantation as consolidation is an option for fit patients who achieve a deep response, though this subset is small. Allogeneic transplantation typically yields better outcomes than autologous transplantation, “so that’s the route we tend to go for our fitter patients,” Dr. Davids said.
Treatment Options Involving Venetoclax
Dr. Davids and his team have been developing a “chemosensitization” approach in which venetoclax is used to prime the cancer cells to die and then is combined with dose-adjusted R-EPOCH. Hospitalized patients receive one cycle of R-EPOCH alone, then at count recovery an accelerated “ramp up” of venetoclax to 400 mg/d, then dose-adjusted R-EPOCH for up to five additional cycles, with venetoclax 400 mg/d given on days 1 to 10 of each cycle; patients can then go to transplantation or continue venetoclax to maintain response. In a prospective trial, this approach was shown to be active, yielding complete responses (the primary endpoint) in 50% of patients and a median overall survival of 19.6 months.7
“Several patients have had long-term survival, 3 to 4 years out from their original treatment,” Dr. Davids reported. “However, we did see significant rates of cytopenias and infections, as well as febrile neutropenia, in over 30% of patients. So, we have amended the study to have a VR-CHOP [R-CHOP plus venetoclax] cohort to see whether we can preserve the chemosensitization effect while mitigating some of the toxicities.”
Mayo Clinic investigators have retrospectively evaluated the use of venetoclax in combination with a variety of regimens, including intensive chemotherapy, R-CHOP, Bruton’s tyrosine kinase (BTK) inhibitors, obinutuzumab, and CD20 monoclonal antibodies. Of the 55 patients in the study, the best results were achieved in the 10 patients treated with VR-CHOP, whose 2-year overall survival was approximately 65%.8
Treatment Involving BTK Inhibitors
Although BTK inhibitors (ibrutinib, acalabrutinib) have been evaluated as single agents in Richter’s syndrome, the data are not as encouraging; responses are rare, and median duration of response is short. This may not be the case, however, for the noncovalent BTK inhibitors, including nemtabrutinib and pirtobrutinib, which have produced responses in 50% to 75% of patients in small studies.9,10 “I think these agents may have some activity as monotherapy, but they could also be good combination partners to build on for future regimens,” predicted Dr. Davids.
Also, although blockade of PD-1 was initially promising in small studies, a subsequent larger study was disappointing, with a median overall survival of only 4 months.11 These agents may be more valuable in combinations with drugs such as BTK inhibitors. Nivolumab plus ibrutinib, for example, has demonstrated response rates of about 40% to 65%, with some complete responses and a median overall survival surpassing 1 year.12,13 Early results are also encouraging for the anti–PD-1 monoclonal antibody tislelizumab and the covalent BTK inhibitor zanubrutinib.
Combination Therapies With PI3K Inhibitors
Pembrolizumab combined with the PI3K inhibitor umbralisib and the CD20 antibody ublituximab elicited responses in five of seven patients, including two complete responses in patients with at least seven prior lines of therapy; complete responses lasted 12 to 20 months.14 Although umbralisib and ublituximab are not being further developed in oncology, the results provided a “good proof of principle” that this may be an “exciting approach,” he commented.
A phase I study is exploring a similar approach with nivolumab plus copanlisib. Dr. Davids’ group is also leading a phase II study of duvelisib plus venetoclax, supported by promising preclinical data—in a Richter transformation mouse model.15
CAR T-Cell Therapy
Data are limited on the potential for chimeric antigen receptor (CAR) T-cell therapy in Richter transformation (and CLL), but in a retrospective study of nine patients, there were eight responses to axicabtagene ciloleucel. Follow-up was short, but many responses were maintained past 6 months.16 “This was a real-world series, not prospective, but it does look promising. Several of these initial responses were complete remissions. This is certainly worthy of further exploration,” Dr. Davids commented.
Alternative CAR products might also prove beneficial in treating Richter transformation, such as those incorporating natural killer cell therapy. Of note, Dr. Davids mentioned, a dramatic response to this approach has been observed in one patient with complex karyotype and five prior lines of therapy.17
Approach to Richter Transformation in 2022
When a clinical trial is not available, this is how Dr. Davids would approach a patient with newly diagnosed Richter transformation:
- Determine whether the condition is clonally related, if possible. If it is clonally unrelated to CLL, treat as de novo DLBCL. If it is related or unknown, base treatment on previous therapy.
- For those with a clonally related or with unknown clonal relationship previously treated with BTK, PI3K, or BCL2 inhibitors, consider combination therapy, including novel agents. Options could include anti–PD-1 plus a BTK inhibitor or an anti-CD20 antibody plus a BTK inhibitor and/or a BCL2 inhibitor. If complete or partial response is achieved, consider transplantation.
- For patients with clonally related disease who have previously received chemoimmunotherapy (no novel agents) or no prior treatment for CLL, and who have del(17p), TP53 mutation, or a complex karyotype, consider combination therapy, including novel agents.
- For patients with clonally related disease who do not have the previously mentioned aberrations, consider chemoimmunotherapy followed by transplantation if a complete or partial response is achieved. If disease is refractory, consider novel combinations.
Dr. Davids shared these closing thoughts: “The only thing that is heartening is there is a lot of investigation—many ongoing clinical trials—now in Richter transformation. This is very different from 5 or so years ago. Hopefully, some of these combinations will prove to be effective. The CLL research community has recognized Richter transformation as a major unmet need for patients.”
DISCLOSURE: Dr. Davids has served as a consultant for and received honoraria from AbbVie, Adaptive Biotechnologies, Ascentage Pharma, AstraZeneca, BeiGene, BMS, Eli Lilly, Genentech, Janssen, MEI Pharma, Merck, Novartis, Ono Pharmaceuticals, Pharmacyclics, Takeda, TG Therapeutics, Verastem, Aptitude Health, Curio, and Research to Practice.
REFERENCES
1. Davids MS: Is there a right management of Richter’s syndrome? 2022 Pan Pacific Lymphoma Conference. Invited Lecture. Presented July 21, 2022.
2. Tsimberidou AM, Keating MJ: Richter syndrome: Biology, incidence, and therapeutic strategies. Cancer 103:216-228, 2005.
3. Moulin C, Morizot R, Remen T, et al: Clinical and biological characteristics and outcomes of Richter transformation: A French multicenter study from the Filo Group. Blood 134(suppl 1):4112, 2019.
4. Davids MS, Huang Y, Rogers KA, et al: Richter’s syndrome in patients with chronic lymphocytic leukemia on novel agent therapy. 2017 ASCO Annual Meeting. Abstract 7505.
5. Mato AR, Wierda WG, Davids MS, et al: Utility of positron emission tomography-computed tomography in patients with chronic lymphocytic leukemia following B-cell receptor pathway inhibitor therapy. Haematologica 104:2258-2264, 2019.
6. Soilleux EJ, Wotherspoon A, Eyre TA, et al: Diagnostic dilemmas of high-grade transformation (Richter’s syndrome) of chronic lymphocytic leukaemia: Results of the phase II National Cancer Research Institute CHOP-OR clinical trial specialist haemato-pathology central review. Histopathology 69:1066-1076, 2016.
7. Davids MS, Rogers KA, Tyekucheva S, et al: Venetoclax plus dose-adjusted R-EPOCH for Richter syndrome. Blood 139:686-689, 2022.
8. Hampel P, Parikh S, Wierda W, et al: Venetoclax-based treatment of patients with Richter syndrome: Outcomes from a multicenter retrospective study. European Hematology Association Congress 2022. Abstract P651. Presented May 12, 2022.
9. Woyach J, Stephens DM, Flinn IW, et al: Final results of phase 1, dose escalation study evaluating ARQ 531 in patients with relapsed or refractory B-cell lymphoid malignancies. Blood 134(suppl 1):4298, 2019.
10. Mato AR, Shah NN, Lamanna N, et al: Pirtobrutinib (LOXO-305), a next generation, highly selective, non-covalent BTD inhibitor in previously treated Richter transformation: Results from the phase I/II BRUIN study. European Hematology Association Congress 2021. Abstract EP524. Presented June 9, 2021.
11. Armand P, Murawski N, Molin D, et al: Pembrolizumab in relapsed or refractory Richter syndrome. Br J Haematol 190:e117-e120, 2020.
12. Younes A, Brody J, Carpio C, et al: Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: A phase 1/2a study. Lancet Haematol 6:e67-e78, 2019.
13. Jain N, Ferrajoli A, Basu S, et al: A phase II trial of nivolumab combined with ibrutinib for patients with Richter transformation. Blood 132(suppl 1):296, 2018.
14. Roeker LE, Shadman M, Svoboda J, et al: Phase I/II study of umbralisib, ublituximab, and pembrolizumab in patients with relapsed or refractory chronic lymphocytic leukemia and Richter’s transformation: 5-year follow-up. 2021 International Workshop on CLL. Abstract 1083523. Presented September 17, 2021.
15. Iannello A, Vitale N, Coma S, et al: Synergistic efficacy of the dual PI3K-/γ inhibitor duvelisib with the Bcl-2 inhibitor venetoclax in Richter syndrome PDX models. Blood 137:3378-3389, 2021.
16. Kittai AS, Bond DA, William B, et al: Clinical activity of axicabtagene ciloleucel in adult patients with Richter syndrome. Blood Adv 4:4648-4652, 2020.
17. Liu E, Marin D, Banerjee P, et al: Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med 382:545-553, 2020.
