1121 - Safety of concomitant delivery of radiotherapy for second primary malignancy in patients with chronic lymphocytic leukemia treated with continuous novel agents

Background:
Patients with chronic lymphocytic leukemia (CLL) are at elevated risk of developing non-hematologic malignancies. Radiation therapy (RT) is a critical component of management in localized solid organ malignancies. With the advent of novel agents for CLL, such as Bruton tyrosine kinase inhibitors (BTKi) and the BCL-2 inhibitor venetoclax, patients with CLL are often receiving continuous daily therapy. Unnecessary BTKi dose interruptions are avoided as these holds can result in immediate morbidity in the form of disease flare and have also been associated with worse survival outcomes. However, safety data are lacking to guide the concurrent administration of radiation therapy for a second cancer in patients receiving ongoing CLL novel agent treatment.

Methods:
After IRB approval, we identified patients treated concurrently with novel agents for CLL and RT for second primary malignancy at Mayo Clinic from 2014-2022. Adverse events within 3 months of RT were evaluated using the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria for hematological toxicity and the Common Terminology Criteria for Adverse Events (CTCAE) version 5 for non-hematological toxicity. Patients without seamless, concurrent treatment with novel agent therapy and RT were excluded; sequential therapy was not considered. The Wilcoxon signed-rank test was used to assess the median difference before and after radiation.

Results:
Twenty-six patients were included in the study. Most patients were male (n=24, 92.3%) and the average age at start of concurrent radiation treatment was 68 years (range: 51-85 years). Four patients had del(17p) and 18 patients had unmutated IGHV. The median number of prior CLL-directed therapies was 1 (range: 0-4) and 20 patients had received prior chemotherapy. Concurrent CLL-directed treatment consisted of ibrutinib (n=23), acalabrutinib (n=2), and venetoclax (n=1) (Table 1); 58% of patients were receiving a reduced dose prior to RT start. There were no reports of dose reduction in anticipation of radiation therapy.

The most common second primary malignancies were prostate (n=9), head/neck (n=8), and lung (n=3) (Table 1). The most common conventionally fractionated prescriptions (cGy/fx) were 6000/30 (n=6) and >6000-7020/20-33 (n=7). SBRT ranged from 3300/5 to 5400/3 (n=8). Five patients received other, varied RT prescriptions. Median follow up time since RT completion was 1.5 years.

Median hemoglobin pre- and post-radiation were 13.3 g/dL and 12.4 g/dL (p=0.001), respectively (Table 2). Per CTCAE criteria, two cases of grade 3 anemia were identified. At baseline, both of these patients had grade 1 anemia. There were no cases of grade 3 or 4 anemia using iwCLL criteria. Median platelet count before radiation was 175.5 x109/L and after treatment was 140.5 x109/L, (p=0.004; Table 2). There was one case each of grade 3 and grade 4 thrombocytopenia per CTCAE (Table 2; Patient 2 and 1). Prior to radiation, Patient 1 had a baseline grade 1 thrombocytopenia. Using iwCLL criteria there were two cases of grade 4 thrombocytopenia. Median neutrophil count pre- and post-radiation were 4.4 x109/L and 3.4 x109/L (p < 0.001), respectively (Table 2). One case each of grade 3 (Table 2; Patient 3, baseline grade 1) and grade 4 (Table 2; Patient 1, baseline grade 1) neutropenia was reported with both CTCAE and iwCLL criteria. We did not find any evidence of major hemorrhage. There were no reports of tumor lysis syndrome, malignant hypertension, or severe cardiac arrhythmias.

Grade ≥3 non-hematological toxicities occurred in two patients that required hospitalization for critical illness, including one patient with grade 5 respiratory failure 2 months after RT. The most common side effects documented were grade 1 fatigue (n=7, 26.9%) and grade 1 radiation dermatitis (n=5, 19.2%). Every patient completed their course of radiation and there were no cases of dose reduction for radiation.

Conclusion:
This study provides the first assessment of patients with CLL on novel agents who were concurrently treated with radiotherapy for a subsequent solid organ malignancy. Our study found limited CLL-treatment related adverse events. Radiation side effects did not appear to be heightened. Our results suggest that concurrent treatment should be a shared decision-making discussion regarding potential harms versus benefits. A comprehensive clinical evaluation that accounts for the patient’s medical comorbidities and personal risk factors should inform the discussion.