Ibrutinib Treatment of Relapsed CLL Following Allogeneic Transplantation: Sustained Disease Response and Promising Donor Immune Modulation
Authors: Ryan Christine E. , Logan Aaron C. , Rezvani Andrew , Kamdar Manali , Nakasone Hideki , Sahaf Bita , Otani Joanne , Kong Katherine A , Klinger Mark , Faham Malek , Coutre Steven , Miklos David B. 
Published: October 2019

Abstract
Background: Treatment of relapsed chronic lymphocytic leukemia (CLL) with ibrutinib results in high rates of progression-free and overall survival. Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase (BTK), is FDA-approved for use in relapsed CLL. Ibrutinib may also modulate donor T cell alloimmunity via inhibition of interleukin-2-inducible kinase (ITK). Here we report the effects of ibrutinib salvage therapy in 5 CLL patients who relapsed following allogeneic hematopoietic cell transplantation (allo-HCT). In addition to minimal residual disease (MRD) response measurements, we also assessed donor T cell chimerism and donor B cell immune reconstitution following ibrutinib therapy.
Methods: Five patients with high-risk CLL relapsed 1-8.5 yrs following allo-HCT. Four patients had never achieved donor CD3 T cell chimerism >95% following reduced-intensity transplant. Ibrutinib 420mg daily was started 1 mo-2 yrs after clinical relapse. Four of the 5 patients remain on ibrutinib with treatment courses ranging from 3-17 mos. CLL MRD was measured by IgH high-throughput sequencing (HTS) using the ClonoSIGHTTM test (Sequenta, Inc.), which has the sensitivity to detect 1 CLL clone per million leukocytes. Lymph node (LN) size was assessed by CT scan and reported as the sum of the products of the LN diameters (SPD). Donor B cell reconstitution was determined by IgH HTS quantification of total IgH molecules and unique IgH clonotypes.
Results: Lymphocytosis was observed in all 5 patients following initiation of ibrutinib treatment, consistent with previous reports. In 2 patients who received >1 yr of ibrutinib treatment, lymphocytosis peaked at 3 wks and 8 wks after initiation of treatment and slowly declined thereafter, fully resolving within 1 yr (Fig 1A). All 4 patients with pathologic lymphadenopathy prior to treatment experienced dramatic LN reduction (Fig 1B; 68% average reduction in LN size after 3 mos on ibrutinib). The longest duration of follow-up is reported for patient SPN 3975, who had a 17p deletion and received ibrutinib for 39 mos. Treatment was discontinued after CLL MRD became undetectable by ClonoSIGHT (Fig 1C). Evidence of donor T cell immune modulation included achievement of full donor CD3 chimerism after 1 yr and resolution of oral and skin chronic graft-versus-host disease (GVHD) after 6 mos. Although this patient has been off ibrutinib for >8 mos, full donor chimerism persists and CLL MRD remains undetectable (Fig 1C). Before ibrutinib treatment, donor B cells (excluding the patient's CLL clone) accounted for <0.2% of total PBMC as determined by IgH HTS. Following discontinuation of ibrutinib, the percentage of donor B cells increased within 6 months, and now comprises >1% of PBMC (Fig 1D). Furthermore, recovering B cells have diverse, low frequency IgH clonotypes (Fig 1E). Together, our findings show rapid, sustained, and diverse immune reconstitution without CLL recurrence following ibrutinib discontinuation.
Conclusions: Ibrutinib provides effective salvage therapy for CLL relapse following allo-HCT. Post-transplant CLL relapse is often extra-nodal and our experience shows ibrutinib is effective in clearing both nodal and extra-nodal disease. Here we present one patient who stopped therapy after achieving MRD negativity and maintains undetectable disease 8 mos following ibrutinib discontinuation. Ibrutinib treatment demonstrates promising donor immune modulation by promoting full donor chimerism and resolution of chronic GVHD. Our five patient experience supports using ibrutinib in relapsed CLL patients following allo-HCT. Clinical trials are needed to determine the best duration of ibrutinib therapy following post-allo-HCT relapse, chronic GVHD treatment efficacy, and the role of ibrutinib maintenance following allo-HCT.
Figure 1 Figure 1. (A) Percent change in absolute lymphocytic count (ALC) for 2 patients who received ibrutinib treatment for >1 yr. SPN = Stanford Patient Number. (B) Percent reduction in LN size, as reported by the sum of the product of LN diameters (SPD) for 4 patients following initiation of ibrutinib. (C) CLL MRD (reported as a percentage of WBCs) and blood donor CD3 T cell levels shown for patient SPN 3975. (D) B cells (excluding the CLL clone) as percent of total PBMC for patient SPN 3975 as measured by IgH HTS. (E) Total IgH molecules and unique IgH clone counts for patient SPN 3975 at different time points (D=day) post allo-HCT.

Disclosures
Kong: Sequenta, Inc.: Employment, Equity Ownership. Klinger:Sequenta, Inc.: Employment, Equity Ownership. Faham:Sequenta, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Coutre:Pharmacyclics, Inc.: Consultancy, Research Funding. Miklos:Sequenta, Inc.: Research Funding.