Ibrutinib Monotherapy in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Mantle Cell Lymphoma: A Retrospective Single Center Experience from India
Authors: Ahmed Rayaz , Bhurani Dinesh , Agarwal Narendra , Kapoor Jyotsna , Gurha Neha , Shah Manan , Narang Prashant 
Published: October 2019

Abstract
Background: Ibrutinib, a Bruton tyrosine kinase inhibitor, disrupts B-cell antigen receptor signaling pathways that are activated in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Ibrutinib has demonstrated substantial efficacy and received approval by the US FDA for treatment of CLL and relapse/refractory MCL. Aim of this retrospective, single-center case series was to report results of clinical outcomes of ibrutinib monotherapy in patients with relapsed/refractory CLL or MCL in a real world setting, in India.
Methods: This case series includes data from 5 patients with CLL (including 1 patient with del17p) and 4 patients with MCL who received ibrutinib monotherapy at the Rajiv Gandhi Cancer Institute and Research Centre- tertiary cancer care center, New Delhi, between February 2016 and 22 June 2018. All patients received once-daily approved dose of ibrutinib (CLL: 420 mg/ MCL: 560 mg) until disease progression or unacceptable toxicity precluded continuation. Assessment of response was based on the International Workshop on CLL and Revised Response Criteria for Malignant Lymphoma. Safety and tolerability was monitored. Data for this case series was collected retrospectively and summarized descriptively; no formal protocol was followed for this report. Dose modification, discontinuation or change in therapy were allowed as per locally approved prescribing information or treatment guidelines and clinical assessments were at the discretion of the treating physician.
Results: The median (range) age of patients with relapsed/refractory CLL was 77 years (48-80 years) and MCL was 59 years (55-67 years). Median (range) of prior therapies received was 1 (0-6) by CLL and 3 (1-8) by MCL patients and the most common prior therapies for CLL were R-CVP, R-Bendamustine (BR), FCR and for MCL were R-CHOP, BR, R-bortezomib + lenalidomide, R-ICE, R-hyper CVAD and R-DHAP. Among CLL patients, over a mean observation period of 18.2 months (time of analysis: 22 Jun 2018), time on ibrutinib treatment (mean ± SD) was 2.7 ± 3.11 months, 1 patient (aged 80 years) died following 1 month of ibrutinib therapy due to cardiac arrest (not related to ibrutinib) and 3 patients were lost to follow-up of which 2 achieved partial response (PR) at the last visit. One CLL patient with del17p who achieved PR after 8 months of ibrutinib therapy underwent allogenic stem cell transplantation (SCT) and is currently in complete remission (CR) and has chronic graft-versus-host disease. In CLL patients, hemoglobin level (g/dL, Hb; median [range]) increased from baseline (8.6 [8.3-12.1]) to last follow-up (9.5 [6.2-11.7]). Platelet count (median [range]) was higher after treatment initiation (baseline: 74,000 [45,000-104,000]; follow-up: 118,500 [13,000-194,000] cells/µL). Among the 4 MCL patients, over a mean observation period of 18.7 months, 3 patients achieved PR and 1 patient achieved CR (median time to CR: 7 months, prior lines of therapy: 3). At the time of analysis, 3 MCL patients (2 with PR and 1 with CR) continued to receive ibrutinib therapy. One patient who achieved PR within 1 month of ibrutinib treatment, advanced to SCT; the patient relapsed after 2 years and was restarted on ibrutinib and achieved CR. The time on ibrutinib (mean ± SD) in patients with ongoing treatment was 20.6 ± 11.9 months. The time to response (mean ± SD) in these MCL patients was 3 ± 2.7 months. The Hb level (median [range]) increased from baseline (10.45 [9.6-11.60]) following ibrutinib treatment (11.05 [9.8-12.4] g/dL) and the platelet count remained stable ([n=3]; 111,000 [65,000-120,000] to last follow-up (110,000 [108,000-125,000] cells/µL). Of the 9 patients, 7 patients reported adverse events (AEs) and cough, loose stools, abdominal pain and discomfort were the most common. One patient experienced hematological AEs (anemia, thrombocytopenia, neutropenia). All AEs were mild to moderate in nature with 1 CLL and 1 MCL patient requiring dose reduction. No new safety signals were reported.
Conclusions: This analysis from a single-center showed the clinical outcomes of ibrutinib monotherapy over a relatively short treatment duration, in Indian patients. Ibrutinib may serve as a bridge to transplant in relapsed refractory CLL and MCL as reported in two patients here. Clinical outcomes reported here from a single center are similar to that reported in pivotal trials of ibrutinib and from named patient program of ibrutinib in India.

Disclosures
Agarwal: Rajiv Gandhi Cancer Institute and Research Center: Employment. Gurha:Medical Affairs, Janssen, Johnson and Johnson Pvt ltd, India: Employment. Shah:Medical Affairs, Janssen, Johnson and Johnson Pvt ltd, India: Employment. Narang:Medical Affairs, Janssen, Johnson and Johnson Pvt ltd, India: Employment.