Ibrutinib Treatment of Relapsed CLL Following Allogeneic Transplantation: Sustained Disease Response and Promising Donor Immune Modulation

Background & Methods: Treatment of relapsed chronic lymphocytic leukemia (CLL) with ibrutinib results in high rates of progression-free and overall survival. Ibrutinib, an irreversible Bruton's tyrosine kinase inhibitor, may also modulate donor T cell alloimmunity via interleukin-2-inducible kinase inhibition. We report results of ibrutinib salvage therapy in 5 high risk CLL patients who relapsed following allogeneic hematopoietic cell transplantation (allo-HCT). Lymph node (LN) size was measured by CT scan, CLL minimal residual disease (MRD) levels by IgH high-throughput sequencing (HTS) (ClonoSIGHT^TM test, Sequenta Inc.), donor CD3 chimerism by short tandem repeat analysis, and donor B cell immune reconstitution by IgH HTS quantification of total IgH molecules and unique IgH clonotypes.

Results: All 4 patients with pathologic lymphadenopathy prior to treatment experienced dramatic LN reduction on ibrutinib (Fig 1A; 68% average reduction after 3 mos). Patients SPN3975 (17p del) and SPN3431 (11q del) achieved undetectable CLL MRD (<10^-6) after 39 mos and 8 mos, respectively (Fig 1B, 1C). SPN3975 had failed to maintain full donor CD3 chimerism after dose-escalated donor lymphocyte infusions but after 1 yr of ibrutinib achieved full donor chimerism. Oral and skin chronic graft-versus-host disease (cGVHD) additionally resolved after 6 mos. Two additional patients have increased donor chimerism since starting ibrutinib. Although SPN3975 has not taken ibrutinib for >10 mos, full donor chimerism persists and CLL MRD remains undetectable (Fig 1B). Prior to ibrutinib, donor B cells in this patient (excluding the CLL clone) accounted for <0.2% of total PBMC. Following discontinuation of ibrutinib, donor B cells increased within 6 mos and now comprise >1% of PBMC (Fig 1D). Furthermore, recovering B cells have diverse, low frequency IgH clonotypes (Fig 1E).

Conclusions: Ibrutinib provides effective salvage therapy for CLL relapse following allo-HCT and demonstrates promising donor immune modulation, promoting full donor chimerism and cGVHD resolution. Here we present 2 post allo-HCT CLL relapse patients who achieved MRD negativity on ibrutinib, one of whom maintains undetectable CLL 10 mos after stopping therapy. Our findings show rapid, sustained, and diverse immune reconstitution without CLL recurrence following discontinuation. Clinical trials are needed to determine the duration of therapy for post allo-HCT relapse, role of ibrutinib maintenance, and cGVHD treatment efficacy.

Figure 1. (A) Percent reduction in LN size, reported as sum of the product of LN diameters (SPD), for 4 patients following ibrutinib initiation. (B) CLL MRD (as percent of WBCs) and blood donor CD3 chimerism for SPN3975 and (C) SPN3431.  (D) B cells (excluding the CLL clone) as percent of total PBMC for SPN3975. (E) Total IgH molecules and unique IgH clone counts for SPN3975 at time points (D=day) post allo-HCT.