Near-tetraploidy is associated with Richter transformation in chronic lymphocytic leukemia patients receiving ibrutinib

Abstract

Key Points• Pretreatment near-tetraploidy is associated with advanced Rai stage, deletion of 17p, and complex karyotype.• Pretreatment near-tetraploidy is an independent risk factor for ibrutinib discontinuation via Richter transformation.Ibrutinib is a highly effective targeted therapy for chronic lymphocytic leukemia (CLL).However, ibrutinib must be discontinued in a subset of patients due to progressive CLL or transformation to aggressive lymphoma (Richter transformation). Transformation occurs early in the course of therapy and has an extremely poor prognosis. Thus, identification of prognostic markers associated with transformation is of utmost importance. Neartetraploidy (4 copies of most chromosomes within a cell) has been reported in various lymphomas, but its incidence and significance in CLL has not been described. Using fluorescence in situ hybridization, we detected near-tetraploidy in 9 of 297 patients with CLL prior to beginning ibrutinib treatment on 1 of 4 clinical trials (3.0%; 95% confidence interval [CI], 1.4%-5.7%). Near-tetraploidy was associated with aggressive disease characteristics: Rai stage 3/4 (P 5 .03), deletion 17p (P 5 .03), and complex karyotype (P 5 .01). Neartetraploidy was also associated with ibrutinib discontinuation due to Richter transformation (P , .0001), but not due to progressive CLL (P 5 .41). Of the 9 patients with near-tetraploidy, 6 had Richter transformation with diffuse large B-cell lymphoma. In a multivariable model, near-tetraploidy (hazard ratio [HR], 8.66; 95% CI,; P , .0001) and complex karyotype (HR, 4.77; 95% CI,; P 5 .01) were independent risk factors for discontinuing ibrutinib due to transformation. Our results suggest that near-tetraploidy is a potential prognostic marker for Richter transformation to assess in patients going on ibrutinib. IntroductionIbrutinib is a first-in-class oral covalent inhibitor of Bruton tyrosine kinase (BTK) 1 approved to treat chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and Waldenstrom macroglobulinemia. Ibrutinib has rapidly changed the landscape of CLL treatment, with high response rates and prolonged remission durations in both relapsed/refractory CLL and previously untreated patients.2-5 Despite these strides, a subset of patients relapse on ibrutinib. Patients relapse primarily with progressive CLL or Richter transformation, an aggressive transformation into lymphoma, predominantly diffuse large B-cell lymphoma.6 Most patients progressing with CLL acquire mutations in either the C481 ibrutinib-binding pocket of BTK or downstream activating mutations in PLCG2 that bypass the need for signaling through BTK. progress via disease transformation. 6 Identifying prognostic markers associated with Richter transformation is critical at this time as an increasing number of patients have begun to receive ibrutinib and those whose CLL transforms have very aggressive disease and poor prognosis. 6,9 Complex karyotype ($3 unrelated chromosomal abnormalities) has been associated with ibrutinib discontinuation due to progr...

Automated differential white blood cell count and cytological analysis can detect near‐tetraploid cells in chronic lymphoproliferative disorders

“…Furthermore, they showed that near-tetraploidy was associated with discontinuation of ibrutinib due to Richter transformation. 6 Interestingly, two of our CLL patients had a Richter syndrome at the time of diagnosis.…”

“…Small series or case reports have described the presence of NT in B cell precursor acute lymphoblastic leukemia (BCP-ALL), 1 T cell lymphoma, 2 marginal zone lymphoma (MZL), 3 hairy cell leukemia, 4 MCL, 5 and CLL. 6 Pui et al described a striking morphological finding with the presence of clumped chromatin and grooved nuclei in the majority of near-triploid and near-tetraploid BCP-ALL. 1 In MCL, tetraploid clones are more frequently observed in blastoid (36%) and pleomorphic variants (80%).…”

Hodgkin's variant of Richter's transformation during ibrutinib therapy in a series of CLL patients; the Polish Adult Leukemia Group report (PALG)

“…The most important molecular factor is likely the type of clonal relationship between CLL and transformed cells, with clonally-related cases having a much worse prognosis. 8 Unfortunately, this could not be determined in our patients due to the lack of archived CLL cells. Furthermore, the International Prognostic Score (IPS), originally developed for de novo HL, was found to stratify prognosis among Hodgkin-RT patients from the Mayo Clinic database.…”

Overcoming Ibrutinib Resistance in Chronic Lymphocytic Leukemia

“…In the case of DLBCL, overexpression of the CD79B was also reported to be responsible for primary ibrutinib resistance; however, such a mechanism was not reported in CLL [83]. Secondary resistance to BTK inhibitors is far better characterized in CLL, where it can be manifested as a Richter transformation during the first year of therapy or as progressive CLL [62,78,[84][85][86]. It was shown that CLL cells under ibrutinib pressure are prone to clonal shifts as determined by whole-exome sequencing studies [87,88].…”