Ibrutinib‐induced rapid response in chemotherapy‐refractory R ichter's syndrome

Richter's syndrome describes the transformation of CLL into aggressive lymphoma, mostly into diffuse large B‐cell lymphoma (DLBCL). Nearly 10‐15% of patients with CLL develop Richter's Syndrome (RS) during long‐term follow‐up, with a transformation rate of 0, 5‐1% per year. Risk factors for Richter's transformation include advanced stage, biological markers (ZAP 70, CD38, CD49d), and genetic (del 17p, del 11q) factors. Recently, NOTCH 1 and MYC‐network abnormalities were also associated with higher risk for Richter's transformation. The impact of CLL therapy particularly purine‐nucleoside analogue or alkylator‐ based chemoimmunotherapy remains controversial, but transformation rate into Richter's syndrome seems to be increased. Richter's syndrome has also been described with newer therapy approaches, eg, Ibrutinib, a bruton tyrosinkinase inhibitor. In 80%, Richter's syndrome is clonally related to the underlying CLL and provides a poor prognosis. After anthracycline‐based chemotherapy, the response rate is less than <20% with a median survival of less than 12 months after transformation. Allogeneic stem cell transplantation (SCT) improves survival, however only 15% of patients ultimately undergo SCT due to primary‐refractory disease. Twenty percent of patients with a clonally unrelated DLBCL have a better prognosis, similar to de novo DLBCL. In the treatment of relapsed CLL, Ibrutinib shows impressive results. Efficacy in relapsed or refractory DLBCL has been demonstrated in small, retrospective studies with an overall response rate of 29%. A better outcome for ABC‐DLBCL treated with single agent ibrutinib or in combination with CHOP has been suggested in two small studies. Here, we report about a 48‐yr‐old female pt. diagnosed with a DLBCL of the stomach stage IIIA, IPI 1, in 2008, successfully treated (CR) with 6 cycles of R‐CHP (rituximab, cyclophosphamide, adriamycin, prednisone) and two cycles of Rituximab. Vincristine was not given due to underlying hereditary sensorimotor neuropathy (Charcot‐Marie‐ Tooth‐type). In May 2014, a CLL, Binet stage B, with white blood cell count (WBC) of 50 000, 80% lymphocytes, enlarged cervical, axillary, mediastinal, iliacal, and inguinal lymph nodes was diagnosed. BM revealed a CD5/CD23/CD79b/CD22‐positive, FMC7‐negative B‐cell population with 11q‐deletion (del17p and 13q‐ were excluded). To exclude relapse of the DLBCL, a lymph node biopsy was performed. Concurrent evidence for IGH iso‐clonality could be shown in the bone marrow and lymph node biopsy, clonality with the former DLBCL of the stomach was excluded. For clonality analyses, we used a PCR‐ based commercial assay (IdentiClone IGH Gene Clonality Assay by