High rate of complete responses induced by platinum-based regimen with BTK inhibitors in Richter syndrome Open Access

TO THE EDITOR:

Richter syndrome (RS) is an aggressive transformation of chronic lymphocytic leukemia (CLL), most commonly to diffuse large B-cell lymphoma (DLBCL), occurring in 2% to 10% of patients.¹ Despite advancements in CLL treatments, the prognosis of RS with DLBCL remains poor, with complete responses (CRs) achieved in only 7% of patients with the standard-of-care R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy, resulting in a median progression free survival (mPFS) of 10 months and a median overall survival (mOS) of 21 months.² Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) has been proposed for patients who achieve a CR, with a 3-year PFS and OS of 66% and 77%, respectively.³ Given the suboptimal responses and poor survival outcomes with conventional chemotherapy, novel therapies aimed at achieving durable CR are urgently needed. Bruton tyrosine kinase (BTK) inhibitors (BTKis) have demonstrated activity in RS, with overall response rates (ORRs) ranging from 40% to 75% and CRs from 8% to 25%,^4-7 albeit with short mPFS of 2.9 to 17.3 months. Due to the rarity of RS, prospective clinical trials evaluating the combination of chemoimmunotherapy with BTKis are difficult to perform. Herein, we retrospectively evaluated the therapeutic role of RICE (rituximab, ifosfamide, carboplatin, and etoposide) in combination with the covalent BTKis ibrutinib or acalabrutinib.

During the period from 1 January 2015 through 25 April 2024, we treated patients with RS-DLBCL with a combination of RICE and a covalent BTKi. Herein, we retrospectively reviewed the medical records of these patients. The study was approved by the University of Miami institutional review board. Collected data included demographic information, pathologic characteristics (p53 mutations, fluorescence in situ hybridization with 17p del, karyotype, and clonality status), and clinical information, including response to treatment, PFS, and OS. Response to RICE + BTKi was assessed based on the Lugano criteria.⁸ PFS and OS were calculated from the time of RICE with or without BTKi initiation until progressive disease (PD) or death and death from any reason, respectively. Survival analyses and graphs were prepared with RStudio and Adobe Illustrator.

Eleven patients with RS-DLBC were treated with RICE + BTKi (ibrutinib in 10 and acalabrutinib in 1). Five of these patients were treatment naive before RD-DLBCL diagnosis. Data regarding the clonal relationship between the preceding CLL and RS were available for 2 patients, and both were clonally related. The clinical characteristics are shown in Table 1. Ibrutinib dose was 420 mg once daily in all but 1 patient (560 mg once daily). Acalabrutinib was prescribed at a standard 100 mg twice-daily dose. BTKi was added on average 22 days (range, 7-61) after RICE initiation in 6 patients, with most starting within 14 days, whereas BTKi was started before RICE in 5 patients. Patients received a median of 4 cycles of RICE (range, 2-4). One patient received high-dose methotrexate during the first 2 cycles of RICE for central nervous system disease.

Six patients with RS were BTKi naive, whereas 5 patients were previously treated with a BTKi (3 for CLL, 1 for RS, and 1 for both CLL and RS). CLL was not in CR in any of these 5 patients. Of the 6 patients who received frontline RICE + BTKi for RS, 3 had previously received BTKi therapy for CLL, whereas 2 patients were treatment naive. Five patients received RICE + BTKi for relapsed or refractory RS, and 3 of them were BTKi naive. Previous treatments for RS included R-CHOP, R-CHOP + ibrutinib, DA-EPOCH-R (dose adjusted etoposide, prednisone, vincristine, cyclophosphamide, and rituximab), IVAM (ifosfamide and mesna, etoposide, and cyclophosphamide), R-MPV (rituximab, high-dose methotrexate, procarbazine, vincristine), ibrutinib-venetoclax, rituximab, venetoclax with duvelisib (as part of a trial), and Allo-HSCT.

In all 11 patients treated, the ORR to RICE + BTKi was 91%, with 64% patients achieving a CR (Figure 1). mPFS and mOS were not reached at a median follow-up of 56.5 months, whereas the 12-month PFS and OS were 64% and 73%, respectively. The ORR in the 6 BTKi-naive patients was 100% (n = 6), with 73% (n = 5) achieving a CR. The 5 patients in CR were subsequently consolidated with Allo-HSCT (matched unrelated donor [MUD] peripheral blood stem cell transplant [PBSCT] in 3 and mismatched unrelated donor PBSCT in 1) and chimeric antigen receptor T-cell (CAR-T) therapy (axicabtagene ciloleucel) in 1, whereas 1 patient in partial response (PR) received CAR-Ts (axicabtagene ciloleucel). Three BTKi-naive patients are alive and remain in CR (2 after MUD PBSCT and 1 after CAR-T), with no additional treatment for 84, 102, and 34 months, respectively. Among the 5 patients pretreated with BTKi, the ORR was 80% (n = 4), with 40% (n = 2) achieving a CR. All 4 patients who responded were consolidated with Allo-HSCT (2 CRs with MUD and mismatched unrelated donor PBSCT and 1 PR with MUD PBSCT) and CAR-T therapy (1 PR; tisagenlecleucel). In the latter patient with a PR, CAR-T treatment led to a CR. All 3 BTKi-pretreated patients achieving CR (2 Allo-HSCT and 1 CAR-T) are alive, with no additional therapy for 56, 38, and 59 months, respectively. One PD occurred in a patient who was later found to have a BTK-C481S mutation, which can confer resistance to BTKi.⁹ 

In the 6 patients treated with RICE + BTKi as the first treatment for RS, the ORR was 83% (n = 5), with all the responders achieving a CR. The ORR to RICE + BTKi in patients with RS failing other preceding treatments was 100% (n = 5), with 40% (n = 2) achieving a CR. In the 5 patients with untreated CLL, the ORR was 100%, with 80% (n = 4) achieving a CR and 20% PR (n = 1). mPFS was not reached at a median follow-up of 58.7 months. Among the 4 patients with TP53 mutations in the RS sample, 50% achieved a CR (n = 2; 1 BTKi naive and 1 non–BTKi naive), 1 a PR (non–BTKi naive), and 1 a PD (non–BTKi naive). Among the TP53 mutated patients, the 12-month PFS and OS were both 75%. Two patients with clonally related CLL/RS (100%) achieved a CR after RICE + BTKi treatment.

The patients did not continue BTKi during Allo-HSCT or CAR-T therapy. However, BTKi was restarted in 4 of 9 patients (2 after Allo-HSCT and 2 after CAR-T) by the treating physicians. In 1 patient, it was stopped after 2 months because of neutropenia, and the patient died from infection. In 2 others, it was also stopped 18 and 21 months after reinitiation because of treatment complications. One patient remains on BTKi.

Adverse events caused by the RICE + BTKi combination (grade ≥3) included neutropenia (n = 10), anemia (n = 8), thrombocytopenia (n = 7), febrile neutropenia (n = 3), infection (n = 4), rectal bleeding (n = 1), and hiccups (n = 1). None of the patients died during the RICE + BTKi treatment. Five patients died, 2 due to RS progression and 3 due to infectious complications after Allo-HSCT, including invasive fungal infection with vancomycin resistant enterocci-induced septic shock, pneumonia with undiagnosed pathogen, and a probable fungal infection.

Herein, we show that RICE + BTKi treatment can lead to high response rates in newly diagnosed and relapsed/refractory RS-DLBCL. Platinum-based regimens have been previously demonstrated to have activity in RS-DLBCL, a lymphoma with known resistance to anthracyclines.¹⁰ The notable clinical effect of BTKi when combined with RICE chemotherapy stems from the fact that B-cell receptor (BCR) signaling is biologically important for the survival of RS cells.^11,12 Specifically, BCR stimulation induces ex vivo proliferation of RS cells with combined biallelic TP53 inactivation and CDKN2A/2B abnormalities, 2 of the most common genetic aberrations in RS.¹¹ Furthermore, genetic disruption of the BCR in RS-DLBCL–derived xenograft cells inhibits their growth in vivo, a finding recapitulated by pharmacologic experiments with ibrutinib.^11,12 Although the short-lasting duration of response with BTKi alone in patients with RS-DLBCL hints rapid acquisition of resistance,^4-6 our study suggests that RICE + BTKi combination overcomes resistance mechanisms and leads to superior clinical outcomes.² 

This study’s limitations include its retrospective design, single-center experience, high percentage of patients with previously untreated with CLL, and potential selection bias. Two patients had treatment-naive CLL and received RICE + BTKi as initial treatment for RS, with both achieving CR. Nevertheless, the characteristics of our patients resemble the general RS-DLBCL population, with high incidence of TP53 mutations. In addition, despite the expected hematologic toxicity, which was comparable to that observed with RICE alone, all responding patients were able to complete the treatment regimen. Notably, no bleeding complications were observed, besides 1 patient with rectal bleeding in the context of chronic proctitis. Although newly reported studies with novel agents, such as the combinational regimen VR-EPOCH (venetoclax with DA-EPOCH-R) and the bispecific antibody epcoritamab, have reported high CR (35%-50%) and ORR (50%-62%) rates,^13,14 our study demonstrated excellent ORR and CR, which allowed patients to be consolidated with Allo-HSCT or CAR-T, resulting in long-lasting CR without CLL and RS recurrence. In our opinion, the combination of high CR rates after RICE + BTKi combination, which allowed consolidation with cellular therapy, led to prolonged PFS.

In summary, we report that RICE + BTKi combination leads to high CR rates, allowing patients to proceed with consolidative Allo-HSCT or CAR-T. Future clinical trials should consider investigating the combination of platinum-based chemotherapies with BTKis, including noncovalent BTKi (pirtobrutinib), as we aim to improve response rates and survival outcomes in RS-DLBCL.

Acknowledgments: G.P. is supported by the philanthropy of Stephen Schwartz and the University of Miami Sylvester Comprehensive Cancer Center. I.S.L. is supported by National Cancer Institute grant 1RO1CA233945-01, the Institute for Follicular Lymphoma Innovation, Dwoskin and Anthony Rizzo Families Foundations, and University of Miami Sylvester Comprehensive Cancer Center. This work was supported by National Institutes of Health (NIH), National Cancer Institute grant NIH U01 CA195568 (ISL).

Contribution: G.P. designed the research, analyzed and summarized data, prepared graphs, and wrote the initial manuscript; G.P. and M.A. collected data; I.S.L. conceptualized the idea of combining Bruton tyrosine kinase inhibitors with RICE, summarized data, and wrote the manuscript; D.P.C. performed clonality studies; J.D.R., J.P.A., and I.S.L. were involved in the treatment of these patients; and all authors reviewed the manuscript

Conflict-of-interest disclosure: G.P. is a shareholder in CRISPR Therapeutics; is an equity holder in Mevox Ltd; and reports consultancy fees from ADC Therapeutics and BeiGene. J.P.A. reports research support from ADC Therapeutics, Genmab, AbbVie, and BeiGene, and consultancy fees from ADC Therapeutics, Novartis, Eli Lilly, Genentech, AbbVie, and Regeneron. I.S.L. reports research support from ADC Therapeutics and Genentech. The remaining authors declare no competing financial interests.

Correspondence: Izidore S. Lossos, Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami, 1475 NW 12th Ave (D8-4), Miami, FL 33136; email: ilossos@med.miami.edu.