Low Rates of Febrile Neutropenia Despite Frequent Grade 4 Neutropenia in Patients Treated with Pembrolizumab + AVD in Untreated Classic Hodgkin Lymphoma
Authors: Kuczmarski Thomas M , Ujjani Chaitra S. , Poh Christina , Warren Edus H. , Smith Stephen D. , Shadman Mazyar , Till Brian G. , Raghunathan Vikram , Tseng Yolanda D , Du Hongyan , Vandermeer Jacquelin , Kelly Alyssa , Rasmussen Heather , Voutsinas Jenna M. , Gopal Ajay K. , Lynch Ryan C 
Published: December 2024

Introduction
Concurrent checkpoint inhibition (CPI) and chemotherapy has demonstrated high efficacy in the frontline setting for patients with classic Hodgkin lymphoma (CHL). While historical data have supported ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) treatment without granulocyte-colony stimulating factor (G-CSF) despite neutropenia, management in CPI-based combinations is currently undefined. In patients treated with CPI and chemotherapy, grade ≥3 neutropenia was common (47%), while febrile neutropenia (FN) rates were low (5%, Herrera et al ASCO 2023). However, there are limited data regarding the nature of FN episodes and correlation with other factors such as preceding neutropenia and G-CSF use. We present data on neutropenia, FN, and G-CSF use from our single-center clinical trial of pembrolizumab and AVD (APVD).
Methods
We reviewed laboratory data for all patients enrolled in a clinical trial of 2-6 cycles of APVD (NCT03331341). We obtained clinical data, including absolute neutrophil count measured regularly every 1 to 2 weeks throughout treatment, from the patients' electronic medical records. We evaluated the timing and severity of neutropenia for the duration of treatment. We collected additional pertinent clinical data from the electronic medical record and from the clinical trial's electronic database.
Results
Baseline characteristics of this cohort (N=50) have previously been reported (Lynch et al., ASH 2023). Among 50 patients treated with APVD, 35 (70%) had grade 4 neutropenia, 7 (14%) had grade 3 neutropenia, 3 (6%) had grade 2 neutropenia, 1 (2%) had grade 1 neutropenia, and 4 (8%) had no neutropenia. Febrile neutropenia occurred in 5 (10%) patients, and grade 3-4 infection occurred in 4 (8%) patients.
Primary prophylaxis with G-CSF was administered in 7 (14%) patients (average age 66). FN rates for these patients were 0%, though one of these patients did experience non-neutropenic sepsis due to a colonic abscess. These patients received G-CSF for a mean of 4.7 cycles of chemotherapy (87% of total chemotherapy cycles). Secondary prophylaxis was administered in 6 (14%) patients (average age 39) for a mean of 3 cycles of chemotherapy. None of the patients receiving secondary prophylaxis developed FN after initiating G-CSF. In 43 patients who did not receive G-CSF for primary prophylaxis, the mean total duration of grade 4 neutropenia was 45.6 days (range: 0 - 147 days) with a median of 21 days. FN and grade ≥3 infection occurred in only 5 (12%) and 3 (7%) of these patients, respectively.
For the 5 patients who developed FN, none were previously on G-CSF. Four patients were female, and one patient was male. Disease stage ranged from IIB to IV. Grade 4 neutropenia preceded each episode of FN for an average of 36.5 days (range: 0 - 100 days). Patient age ranged from 19 to 58 (mean 37). FN developed during cycles 1 through 5 of combination therapy. One patient developed two episodes of FN approximately 20 days apart, and G-CSF was initiated after the second episode of FN.
Conclusion
Compared to combination nivolumab and AVD, rates of grade 4 neutropenia were high at 70% in patients treated with APVD. Rates of primary and secondary prophylaxis with G-CSF were low. Despite higher rates of neutropenia, FN and grade ≥3 infections were uncommon and appeared similar to historical data with ABVD.