Pseudo‐Richter transformation of chronic lymphocytic leukaemia/small lymphocytic lymphoma following ibrutinib interruption: a diagnostic pitfall

Abstract

Ibrutinib, an oral inhibitor of Bruton tyrosine kinase (BTK), has emerged as an efficacious, widely used therapy for chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL).1 Treatment is generally continued until disease progression or unacceptable toxicity.2 While tolerated by most patients, adverse effects such as serious infection may lead to treatment interruption. Additionally, ibrutinib is typically held for 3–7 days before and after surgery to mitigate bleeding risk. Usually, a brief dose interruption is uneventful. Rarely, however, significant disease progression may occur.3 Here, we describe five CLL/SLL patients in whom temporary holding of ibrutinib for surgery or acute infection resulted in significant clinical progression with lymphadenopathy, lymphocytosis, or progressive cytopenia. Tissue biopsy demonstrated diffuse large B-cell lymphoma (DLBCL), consistent with Richter transformation (RT). Upon resuming ibrutinib, clinical signs resolved; re-biopsy showed only CLL/SLL with regression of large-cell transformation. Our cohort had one female and four male patients with a median age of 70 years (69–83). The baseline disease characteristics are summarized in Table I. All patients received single-agent ibrutinib therapy: two as front-line and three at relapse. The median duration of treatment was 35 months (10–48), and all achieved partial response with disease well controlled prior to dose interruption. Ibrutinib was held due to surgery in three patients and acute infection in two. The median duration of interruption was 14 days (10–43). All patients developed signs of progression during interruption, including increased lymphadenopathy (5/5), lymphocytosis (4/5), worsening anaemia/thrombocytopenia (2/5), and B symptoms (3/5). Lactate dehydrogenase (LDH) was markedly elevated in the two patients with infection and mildly elevated to normal in the three patients undergoing surgery. All patients had tissue biopsies 7–13 days into ibrutinib interruption. In the three patients who underwent surgery, enlarged lymph nodes were sampled during surgery. The remaining two had lymph node or bone marrow biopsy to investigate disease progression. All biopsies revealed effaced tissue architecture by a diffuse infiltrate of large atypical lymphocytes (Fig 1A–D), with increased proliferation rates (80–90% by Ki-67 immunostaining) (Fig 1I). All cases were diagnosed as DLBCL, consistent with RT. The large cells had an immunophenotype similar to CLL/SLL (CD20+/CD5+/CD23+/LEF1+) in all cases (Fig F–H), indicating a clonal relationship between DLBCL and CLL/SLL. All cases were activated B-cell subtype by Hans algorithm. Epstein–Barr virus (EBV)/EBV-encoded small RNAs (EBER) and MYC gene rearrangement were negative. Patients were re-started on ibrutinib, either alone (3/5) or with obinutuzumab (2/5). LDH and lymphocyte count in all patients returned to normal within four weeks of treatment resumption (Table I). Cytopenias were markedly improved. Imaging done in 4/5 patients 1–4 months after resuming ibrutinib showed significant reduction of lymphadenopathy. Follow-up biopsies performed in three patients 1–6 months later showed no evidence of DLBCL; residual CLL/SLL was present. All patients were alive on last follow-up (3–22 months) and remained on ibrutinib-based treatment. To our knowledge, this is the first report of biopsy-proven Richter-like aggressive transformation of CLL/SLL following ibrutinib interruption, with regression of clinical and pathological changes after ibrutinib resumption. Previously, Woyach described a CLL patient with signs of disease progression following ibrutinib interruption for surgery, which resolved with reinstating ibrutinib.3 Disease progression has also been observed in a subset of patients with Waldenström macroglobulinaemia on ibrutinib, whose treatment was interrupted due to surgery/toxicity. Response was regained within three months of ibrutinib reinitiation.4 No pathology results were reported in these studies. It is unclear why some patients experience withdrawal-induced progression. It was speculated that CLL/SLL patients early in treatment or with a higher level of residual disease may be prone to having this phenomenon.3 However, our patients were well into ibrutinib treatment (on therapy 10–48 months) and had achieved partial response, most with low/minimal disease before interruption. Therefore, disease burden and time on ibrutinib did not correlate with pathologic progression in our small cohort. Notably 4/5 patients had trisomy 12, alone or with other aberrations, and the remaining one had 17p deletion (Table I). CLL with +12 is associated with atypical morphology and increased proliferative rate.5 Both +12 and 17p− CLL have an increased risk of RT.6 B-cell receptor (BCR) signalling is aberrantly upregulated in CLL/SLL and plays an important role in pathogenesis. BTK is an essential component of BCR signalling, and its inhibitors have demonstrated durable remission in CLL.7 However, 10–18% of patients progress on medication and a subset develops RT.8 RT cases arising during ibrutinib treatment usually occur early, are clonally related to CLL/SLL, and may acquire additional BTK mutations or show expansion of TP53-mutated clones.8-10 The clinical and biopsy findings in our patients following ibrutinib interruption resemble those of ibrutinib-refractory RT cases. The crucial difference, however, is that transformation in our cases remained ibrutinib-responsive as resumption of treatment led to regression of large-cell transformation. Our findings represent a novel observation of transient and reversible Richter-like transformation following ibrutinib interruption. We therefore propose to name this phenomenon “pseudo-RT”. We speculate that CLL/SLL cells in these patients are highly proliferative upon BCR-pathway activation and that even a transient withdrawal of inhibition by ibrutinib interruption may trigger accelerated cell proliferation. In support of this hypothesis, 3/5 patients (patients #3, #4, #5) had CLL/SLL with expanded proliferation centres, which characterizes a relatively aggressive CLL/SLL at baseline.11 In summary, we report CLL/SLL cases with morphological and clinical features of RT, developing after dose interruption of ibrutinib. Resumption of ibrutinib led to resolution of clinical manifestations in all cases, and confirmed pathologic regression to CLL/SLL in three examined cases. Our findings demonstrate the important diagnostic challenge and pitfall in patients who develop disease progression while ibrutinib is temporarily interrupted. Caution should be taken to distinguish pseudo-transformation from true RT in the era of targeted therapy. While conventional RT requires aggressive immunochemotherapy, pseudo-transformation may be simply and effectively treated by resuming ibrutinib therapy. Larger cohort studies with comprehensive molecular evaluation are needed to better characterize this unique phenomenon and its impact on long-term clinical outcome. We thank all the patients that were included in the study. LBS and QC designed the study, collected and analyzed data, wrote the manuscript, and approved the final version. SM analyzed data, wrote the manuscript, and approved the final version. AB wrote the manuscript, and approved the final version. SM received research funding from Abbvie, AstraZeneca, BeiGene, Genentech, Gilead, Janssen, Juno, Novartis, Pharmacyclics and TG Therapeutics; and received honorarium for advisory board or lecturing for Abbvie, AstraZeneca, BeiGene, Genentech, Gilead, Janssen, Kite and Pharmacyclics. AB received honorarium for lecturing for Bayer, Foundation Medicine and Pfizer. The other authors declare no conflicts of interest.

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