Patient characteristics that predict Richter's transformation in patients with chronic lymphocytic leukemia treated with ibrutinib

Abstract

Chronic lymphocytic leukemia (CLL) transformation to aggressive lymphoma, known as Richter's Transformation (RT), has a dismal prognosis. There are limited data evaluating risk of RT in patients treated with ibrutinib. We performed a retrospective analysis to determine prognostic variables associated with development of RT and overall survival (OS) at progression after treatment with ibrutinib. We identified 559 patients with CLL treated with ibrutinib from 2010–2019. After a median follow‐up of 44.5 months from ibrutinib start, 179 patients progressed and were included in our analysis. After a median follow‐up of 20.8 months from progression, 54 out of 179 patients developed RT. Progression on treatment (hazard ratio [HR] 4.01 [1.60–10.00], p = .003), higher LDH (HR 1.80 for 2‐fold increase [1.33–2.43], p = .0001), and lymphadenopathy without lymphocytosis (HR 2.88 [1.15–7.20], p = .02) were independent prognostic variables for the development of RT at progression. Progression with lymphadenopathy without lymphocytosis continued to be an independent prognostic variable of worse OS post‐progression. In a subset analysis of 50 patients who obtained a PET‐CT at progression, the median SUVmax for patients who would develop RT was 15.2 (n = 30, range: 4.0–46.3) versus those patients who did not develop RT with a SUVmax of 7.7 (n = 20, range: 2.3–27.2) (p = .0030). Median OS from date of RT was 4.0 months, suggesting that prognosis for RT remains poor. A lymph node biopsy to rule out RT should be considered in patients who received ibrutinib who progress on treatment, have an elevated LDH, or progress with lymphadenopathy without lymphocytosis.

Treatment of Richter’s Transformation with Novel Therapies

“…Recently, we assessed patients with CLL treated with ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), who progressed, to determine which clinical features were associated with RT development at progression. We found that lymphadenopathy without lymphocytosis, elevated LDH, and progression on treatment for CLL were associated with development of RT at progression [ 13 •]. Additionally, we reported that the median SUV max for patients who developed RT was 15.2 versus a median of 7.7 for those that had progressive CLL without RT [ 13 •].…”

“…We found that lymphadenopathy without lymphocytosis, elevated LDH, and progression on treatment for CLL were associated with development of RT at progression [ 13 •]. Additionally, we reported that the median SUV max for patients who developed RT was 15.2 versus a median of 7.7 for those that had progressive CLL without RT [ 13 •]. This suggests that the traditional cutoff of SUV ≥ 5 to consider biopsy for RT exclusion continues to be a valid marker.…”

Richter’s Syndrome (RS): Emerging Therapeutic Horizons

“…In a separate retrospective study conducted in a Danish cohort, advanced Binet stage (B-C), del(17p), and unmutated IGHV were identified as independent risk factors for the development of RS [21]. In the era of ibrutinib treatment, a rapid rise in serum lactate dehydrogenase (LDH) and lymphadenopathy without lymphocytosis were recognized as independent prognostic variables for RS development at the time of disease progression [22]. Additionally, Visentin et al identified the presence of a complex karyotype as being associated with an increased risk of RS.…”

Emerging entities: high-grade/large B-cell lymphoma with 11q aberration, large B-cell lymphoma with IRF4 rearrangement, and new molecular subgroups in large B-cell lymphomas. A report of the 2022 EA4HP/SH lymphoma workshop

“…He presented with a right groin mass that was biopsied and diagnosed as PBL with a MYC-R. Molecular studies demonstrated that the CLL and PBL were clonally related and shared the same TP53 mutation. Interestingly, recent reports have associated treatment of CLL with the BTK inhibitor ibrutinib and Richter's transformation mimicking PBL [66][67][68]. Further studies are warranted to understand PBL-like transformation in CLL and in other lymphomas.…”