Emergence of Bruton's tyrosine kinase‐negative Hodgkin lymphoma during ibrutinib treatment of chronic lymphocytic leukaemia

Abstract

Chronic lymphocytic leukaemia (CLL) is a chronic B-cell lympho-proliferative disorder in which lymphomatous transformations occur in 5%-15% of patients. Histologically these cases resemble diffuse large B-cell lymphoma, or Richter's transformation, in over 80% of cases. Rare cases of transformation to Hodgkin lymphoma (HL) have been reported in the literature with an estimated prevalence of 0.4%. We report a case of a 67-year-old female with CLL treated with the novel Bruton's tyrosine kinase (Btk) inhibitor, ibrutinib, who subsequently presented with intractable fevers. Bone marrow trephine, and lymph node biopsy revealed classical HL with negative immuno-histochemistry for Btk in HL cells, on a backdrop of CLL. The patient commenced treatment with Adriamycin, Vinblastine and Dacarbazine (AVD), which resulted in an excellent response. Hodgkin transformation of CLL is rare with a single retrospective study of 4121 CLL patients reporting only 18 cases. Btk expression in HL cells is recently recognised in classical HL; however, the majority of HLs are Btk negative. Given that Btk inhibitors have recently been shown to induce genomic instability in B cells, in the context of their widespread use, such emerging cases are increasingly relevant.

Hodgkin lymphoma transformation of chronic lymphocytic leukemia—A real life data from the Polish Lymphoma Research Group

“…Our analysis confirms that HvRS can develop anytime since CLL/SLL diagnosis, being however a late event in the majority of patients. In our study, the median time of 3.2 years to HvRS from CLL/SLL diagnosis was shorter than the time reported by others (4.6‐7.5 years) . It is difficult to explain but it might be simply a consequence of relatively late diagnosis of neoplastic diseases in Poland, especially if asymptomatic as in the case of CLL .…”

“…The effect of a current shift in CLL treatment to novel agents on the occurrence and course of the RS is unknown. Recently, it was shown in animal and ex vivo studies that PI3Kδ (phosphatidylinositol 3‐kinase δ) and BTK (Bruton's tyrosine kinase) inhibitors increased genomic instability in normal and neoplastic B cells, which may contribute to the promotion of RS including HvRS …”

“…Recently, it was shown in animal and ex vivo studies that PI3Kδ (phosphatidylinositol 3-kinase δ) and BTK (Bruton's tyrosine kinase) inhibitors increased genomic instability in normal and neoplastic B cells, which may contribute to the promotion of RS 32 including HvRS. [33][34][35] There are no guidelines concerning HvRS treatment, and all data on treatment efficacy come solely from small retrospective studies. While ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) regimen is the standard of care for de novo Hodgkin lymphoma, it is also the most frequently used regimen in the treatment of HvRS, with varying response rates ranging between 52% and 77% for overall response rate (ORR) and 20% to 68% for complete remission (CR).…”

Use of flow cytometry in the phenotypic diagnosis of hodgkin's lymphoma

“…Current trials will prospectively investigate nivolumab in combination with other drugs in HL patients at different clinical situations. The combination partners include brentuximab vedotin alone (NCT02572167), brentuximab vedotin and ipilimumab (NCT01896999), ibrutinib (NCT02940301), and A(B)VD chemotherapy (NCT03033914, NCT03004833) . Pembrolizumab was evaluated in the phase IB study Keynote‐013 and included 31 heavily pretreated HL patients.…”

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

“…Although cases of RT are not that uncommon in patients with CLL during ibrutinib therapy, reports on this rare variant are very few. [1][2][3] Our aim was to thus present a series of Hodgkin-RT cases from an ongoing observational study of the Polish Adult Leukemia Group (PALG). 3 Subjects were 165 relapsed/refractory patients with CLL who had started compassionate use ibrutinib therapy and were monitored for "real-life" efficacy and toxicity.…”