Ibrutinib Treatment of a Patient with Relapsing Chronic Lymphocytic Leukemia and Sustained Remission of Richter Syndrome

Abstract

CASE REPORTformation rate. Ibrutinib is a Bruton tyrosine kinase inhibitor that has shown remarkable efficacy in CLL (2); however, little is known about its relationship to RS. We describe the use of ibrutinib in a patient with relapsed CLL who achieved complete remission of an aggressive lymphoma transformation. Case reportA 73-year-old man was diagnosed with CLL in 2003, after a complete blood count (CBC) showed lymphocytosis and mild thrombocytopenia. Imaging revealed enlarged spleen together with cervical, axillary, and inguinal lymphadenopathy. A bone marrow biopsy showed pathologic findings consistent with CLL. ZAP70 and CD38 expression was absent. Gene mutation analysis revealed mutated IGVH and a subclonal NOTCH1 mutation. In 2008, the patient received treatment with fludarabine, cyclophosphamide, and rituximab, resulting in splenomegaly reduction and stable thrombocytopenia. Five years later, he presented with

NOTCH1 Aberrations in Chronic Lymphocytic Leukemia

“…The average mutation rate increased to approximately 15–20% when considering only patients with fludarabine-refractory CLL ( 7 ). NOTCH1 lesions are much more prevalent after disease progression to Richter transformation relative to newly diagnosed CLL, with 30% patients harboring mutations, mostly the classical delCT ( 7 , 53 ). A high mutation rate has been described in independent cohorts of CLL cases with trisomy 12 ( 23 , 54 ).…”

Bepridil exhibits anti‐leukemic activity associated with NOTCH1 pathway inhibition in chronic lymphocytic leukemia

“…24,39,40 Bepridil has been previously reported to increase intracellular Ca 21 in human neutrophils by ER stores emptying. 41 Our data indicated similar alteration in Ca 21 fluxes, suggesting that bepridil might alter NOTCH1 translation, trafficking and/or maturation by reducing ER Ca 21 concentration in CLL. In line with the hypothesis that the ER exhaust might impede protein trafficking, multiple SERCA-type Ca 21 channel inhibitors (i.e., thapsigargin, cyclopiazonic acid and clerodane diterpene casearin J (CJ), 24,34,45 demonstrated a profound anti NOTCH1 activity in different disease models.…”

“…[16][17][18][19] The prevalence of NOTCH1 mutations increases with disease aggressiveness, in relapsed CLL and in patients whose CLL has transformed to Richter syndrome. 20,21 Thus, inhibiting NOTCH1 activity represents a potential therapeutic opportunity in CLL, and the incorporation of NOTCH1 pathway antagonists may improve standard treatment for this disease.…”

“…NOTCH1 mutations represent a new biomarker for the identification of poor‐risk CLL as NOTCH1 ‐mutated patients have a significantly shorter survival compared to NOTCH1 ‐wild‐type . The prevalence of NOTCH1 mutations increases with disease aggressiveness, in relapsed CLL and in patients whose CLL has transformed to Richter syndrome . Thus, inhibiting NOTCH1 activity represents a potential therapeutic opportunity in CLL, and the incorporation of NOTCH1 pathway antagonists may improve standard treatment for this disease.…”

Decreased NOTCH1 Activation Correlates with Response to Ibrutinib in Chronic Lymphocytic Leukemia

“…Despite ibrutinib's activity in CLL, treatment has to be prematurely stopped in cases of Richter transformation (RT; refs. 33,34). We explored the role of NOTCH1 signaling in such setting, as reasons for treatment failure are still under investigation.…”