Long term safety and long term disease control of oral ixazomib and short-course rituximab in untreated iNHL Free

Introduction The importance of safer and more convenient effective therapy is paramount in indolent B-cell non-Hodgkin lymphoma (iNHL) where many patients will require multiple lines of treatment yet achieve a normal life span. We previously reported the initial data on the combination of weekly ixazomib (oral proteasomal inhibitor) and short-course rituximab as an effective and safe treatment for iNHL (Blood Advances 2023, NCT02339922). Here, we report safety and efficacy of long term ixazomib in this population.

Methods Eligible patients with untreated iNHL were treated with ixazomib 4mg orally once weekly. Patients required an indication for treatment as per NCCN guidelines. Rituximab was administered weekly x 4 to patients without progression or unacceptable toxicity during the 7th cycle. The Kaplan Meier method was used to analyze time to event outcomes. We conducted a subset analysis of long term patients who had remained on ixazomib for at least 12 months to evaluate long term disease control and late toxicities.

Results Thirty-three patients received ixazomib. Seventeen patients received long term ixazomib (median 59 months, range 15 - 79) with 10 patients on therapy for ≥4 years. Characteristics of the entire cohort/long term cohort included: median age 62/58, follicular lymphoma (FL) 61%/71%, FLIPI ≥2 52%/47%, high tumor burden 39%/53%. The most common reasons for discontinuing beyond 12 months were study end date (8), progressive disease (5), and adverse event (AE) (3).

Of the 3 long term patients who stopped due to AE, one was due to a grade 1 nonspecific neurotoxicity, one due to a grade 2 rash, and one due to multiple grade 1-2 AE (thrombocytopenia, peripheral neuropathy, diarrhea, dyspepsia). One patient experienced transformation. With a median follow-up of 85 months, the median progression free survival (PFS) of the entire cohort was 26 months (95% CI 8.9 – 85) with 5-year estimate of PFS of 43% (95% CI 28 – 65). In the 17 long term patients, median PFS was 79 months (95% CI 63 – NR) with 5-year PFS estimate of 74% (95% CI 55 – 100). The median duration of response and complete response among responders (6 PR, 11 CR) for the entire cohort was 73 months (95% CI 33 – NR) and 87 months (95% CI 63 – NR) respectively. No rebound progression occurred within 6 months of elective, trial conclusion, or AE related ixazomib discontinuation in long term patients. Responses to subsequent therapy were seen in 5/7(71 %) including 2 patients with CR and 3 with PR. No unexpected toxicities occurred with subsequent therapies that were attributed to prior treatment with ixazomib. One patient who received subsequent therapy has not yet had response-to-treatment assessment.

AEs of grade 3 or higher that developed after 12 months of therapy occurred in 7 patients (back pain, thrombocytopenia, neutropenia, leukopenia, ALT increase, thromboembolic event, nausea/vomiting, second cancer), of which 2 patients' AEs were considered related to ixazomib (thrombocytopenia and neutropenia). Dose holds and reductions due to toxicity after 12 months occurred in 8 and 5 patients, respectively. Serious AEs after 12 months occurred in 2 patients and included diagnoses of lung cancer and pancreatic cancer with nausea/vomiting both of which were considered unrelated to trial.12 long term patients were documented to have experienced COVID-19 infection at any point after starting trial, though no patient died from COVID.

Conclusion Long term use of weekly oral ixazomib with short course rituximab was safe, convenient and associated with prolonged disease control with minimal grade 3 AEs in a meaningful subset of patients with previously untreated iNHL. While the optimal duration of ixazomib is not known, few stopped therapy due to disease progression or toxicity. The median duration of response was greater than 6 years, highlighting the durability of this regimen among responders. Importantly, even though the study was conducted during the acute phase of the COVID-19 pandemic, no patients died from COVID-19 unlike observations with other chronically administered oral agents. This once-weekly oral approach for treating iNHL may prove highly useful, especially in resource limited locations once generic and internationally sourced versions are available. This study suggests the potential of long term disease control through an oral, safe, and convenient treatment regimen, supporting further study of ixazomib in larger studies.