Durable responses to ibrutinib in patients with relapsed CLL after allogeneic stem cell transplantation

Abstract

Ibrutinib, a recently approved inhibitor of Bruton's tyrosine kinase (BTK), has shown great efficacy in patients with high-risk CLL. Nevertheless, there are few data regarding its use in patients who relapsed after allogeneic stem cell transplantation (alloSCT). We report clinical data from five CLL patients treated with ibrutinib for relapse after first or even second allogeneic transplantation. Additionally, we performed analyses on cytokine levels and direct measuring of CD4 Th1 and CD4 Th2 cells to evaluate possible clinically relevant immunomodulatory effects of ibrutinib. All patients achieved partial responses including one minimal residual disease (MRD)-negative remission. Within 1 year of follow-up, no relapse was observed. One patient died of severe pneumonia while on ibrutinib treatment. Beside this, no unexpected adverse events were observed. Flow cytometry and analyses of T cellmediated cytokine levels (IL10 and TNFα) did not reveal substantial changes in T-cell distribution in favor of a CD4 Th1 T-cell shift in our patients. No acute exacerbation of GvHD was reported. In conclusion, these results support further evaluation of ibrutinib in CLL patients relapsing after alloSCT.

Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT

“…One patient achieved MRD negativity. 13 Ibrutinib was tolerated with a safety profile similar to the one observed in the overall population of patients with R/R CLL treated with ibrutinib in the phase 3 clinical trial as part of the RESONATE study. In that cohort, 57% of patients in the ibrutinib group had at least 1 AE of grade 3 or higher.…”

“…One study reported an observed decrease in serum Th2-type cytokines, including IL-10, IL-4, and IL-13, 12 and another similarly showed a decrease in IL-10 levels following treatment. 13 Here, we report for the first time comprehensive immune phenotype of B and T cells using primary samples from patients with CLL treated with ibrutinib following allo-HCT. Our results show that ibrutinib leads to dramatic depletion of Th2 cells.…”

“…Recent studies have reported on small numbers of patients with CLL who relapsed following allo-HCT and were treated with ibrutinib as a salvage therapy with promising results. 2,13 Here, we present 27 patients with relapsed CLL following allo-HCT who benefited from ibrutinib salvage therapy. Sixteen of these patients were part of multiinstitutional clinical trials, and an additional 11 patients were treated at Stanford University following US Food and Drug Administration (FDA) approval of ibrutinib.…”

CLL: ibrutinib and transplantation ride together

“…7,8 In this issue of Bone Marrow Transplantation, Link et al 9 provide further evidence of the beneficial role of ibrutinib in this context. In this study, five patients with extensively pre-treated high-risk CLL received ibrutinib for progressive CLL at a median of 28 months after alloHCT.…”

Transplantation in CLL: what we can learn from a dinosaur

“…16 In contrast, response rates of 88-100% have been observed in small series of patients who were treated with ibrutinib for CLL relapse after HSCT, resulting in prolonged disease control in the majority of them (with the option of reinstituting effective immunotherapy). 8,17,18 Not to say that it is not unlikely STI will increase the proportion of patients with refractory CLL that can be successfully bridged to transplant, thereby improving the overall outcome. This however means that also the ITT transplant results obtained in the HOVON trial might be not applicable to the current treatment landscape.…”