Patients after alloHCT: Is ibrutinib an effective salvage therapy?

In November 2016, Christine Ryan, from the Stanford Cancer Center at Stanford University School of Medicine, and colleagues recently published in Blood the results of a trial evaluating the efficacy of ibrutinib in the treatment of R/R CLL following allogenic Hematopoietic Cell Transplantation (alloHCT) in 27 patients. Dosage was 420mg ibrutinib daily, except for two pts in the multi-center cohort who received double doses. The key highlights were:

Highlights:

• 16 pts in multi-center clinical trial cohort:
  • 10 pts del17p, 3 pts del11q chromosomal abnormality
  • Average ibrutinib start 27 months after alloHCT
  • ORR=87.5%. CR=2pts, PR=10pts
  • 24-month PFS=77%, OS=75%
  • Most common AE: Diarrhea (11pts)
  • Treatment-related severe AEs (≥ grade 3): 12 pts
  • 2 deaths due to progression, 2 deaths from AEs (pneumonia)  
• 11 pts from Stanford University cohort:
  • 4 pts del17p, 4 pts del11q chromosomal abnormality
  • Multi-center cohort: ORR=87.5%
  • Average ibrutinib start 73.4 months after alloHCT
  • ORR=91%, CR=7pts, PR=3pts
  • Treatment depleted Th2 helper cells and pre-germinal center B-cells (n=10)
• Lymph node size reduction of 73% (n=8)
• MRD negativity was achieved in 36% pts that persisted after treatment end (n=11)
• Of the 27 patients who undertook ibrutinib initiation, none developed GVHD

Ryan et al. concluded that ibrutinib was shown to be effective and well tolerated in the treatment of R/R CLL patients after alloHCT, and that MRD negativity was achieved without developing GVHD. Some positive effects of treatment persisted after discontinuation of ibrutinib, however more work will need to be done with a larger sample size to confirm these results.

Abstract: 

Ibrutinib, a potent and irreversible small molecule inhibitor of both Bruton's tyrosine kinase (BTK) and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplantation who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following FDA approval of ibrutinib; seven (64%) achieved a complete response, and three (27%) achieved a partial response. Of the nine patients treated at Stanford who had mixed chimerism-associated CLL relapse, four (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of eleven (36%) patients evaluated by ClonoSeq™ achieved minimal residual disease (MRD) negativity with CLL <1/10,000 WBC, which persisted even after ibrutinib was discontinued, in one case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following Ibrutinib initiation. We postulate that ibrutinib augments graft-versus-leukemia (GVL) benefit through a T cell-mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre-germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD.