ABSTRACT
Background: Patients (pts) with follicular lymphoma (FL) generally respond well to first-line CD20-targeted therapies, such as obinutuzumab or rituximab-based regimens. However, many pts relapse and studies suggest that each subsequent relapse is associated with shorter durations of response to the next treatment. Parsaclisib is a potent and highly selective next generation PI3Kδ inhibitor. The combination of bendamustine + obinutuzumab is approved for pts with relapsed/refractory (R/R) FL. We hypothesized that adding parsaclisib may improve clinical benefit with a manageable safety profile in this pt population. Aims: CITADEL-102 (NCT03039114) is an open-label, phase 1, dose-finding study that investigated safety and efficacy of parsaclisib in combination with bendamustine + obinutuzumab in pts with R/R FL following rituximabcontaining regimens. Methods: Pts enrolled were ≥18 years with histologically confirmed CD20-positive FL, R/R to any prior rituximabcontaining regimen, ECOG PS 0-2, ≥1 measurable lesion, and ≤4 prior therapies. Pts received parsaclisib 20 mg orally once daily (QD) for 8 weeks then 20 mg once weekly (QW);bendamustine 90 mg/m2 infusion on days 1 and 2 of cycles 1-6;and obinutuzumab 1000 mg infusion on days 1, 8, and 15 of cycle 1, and day 1 of cycles 2-6, and on every second cycle of cycles 8-30 in pts having complete response/complete metabolic response (CR/CMR), partial response/partial metabolic response (PR/PMR), or stable disease/no metabolic response. Part 1 (safety run-in) used a 3+3 design with dose de-escalation to identify the maximum tolerated dose (MTD) of parsaclisib in combination with bendamustine + obinutuzumab. In Part 2 (dose expansion), the safety and efficacy of this combination were further evaluated. The primary study endpoint was safety and tolerability;secondary endpoints included efficacy outcomes (ORR, DOR, PFS, and OS). Results: A total of 26 pts were enrolled and treated;median (range) age was 65.0 (44-80) years, 25 (96.2%) had ECOG PS ≤1, 11 (42.3%) had ≥2 prior systemic therapies, and 6 (23.1%) had received prior bendamustine. Median (range) parsaclisib exposure was 10.6 (0.4-32.8) months. Main reasons for treatment discontinuation included adverse events (AEs) (8 pts, 30.8%) and progressive disease (6 pts, 23.1%). All pts experienced treatment-emergent AEs (TEAEs);most common any-grade TEAEs (≥10 pts) were pyrexia (53.8%), neutropenia (50%), diarrhea (46.2%), thrombocytopenia, and nausea (each 38.5%). Grade ≥3 TEAEs were experienced by 88.5% of pts;most common grade ≥3 TEAEs (≥2 pts) were neutropenia (34.6%), febrile neutropenia (23.1%), thrombocytopenia (19.2%), ALT and AST increase (each 11.5%), and diarrhea, neutrophil count decreased, and rash maculopapular (each 7.7%). One of 6 evaluable pts in Part 1 had a DLT of grade 4 QTc elongation. The MTD was not reached, and parsaclisib 20 mg QD for 8 weeks then 20 mg QW was the selected dosage for dose expansion in Part 2. Treatment discontinuation due to TEAEs was 30.8%, 7.7%, and 15.4% for parsaclisib, bendamustine, and obinutuzumab, respectively. One fatal TEAE (COVID-19 pneumonia) occurred. ORR (95% CI) as reported by the investigator was 76.9% (56.4-91.0), with 17 pts (65.4%) achieving CR/CMR and 3 pts (11.5%) achieving PR/PMR as the best overall response. Median DOR, PFS, and OS were not reached. Summary/Conclusion: Parsaclisib in combination with bendamustine + obinutuzumab appears to have a manageable safety profile and demonstrated promising efficacy in pts with R/R FL.
ABSTRACT
Aim: The novel coronavirus (SARS-CoV-2) is a highly contagious disease with a significant mortality rate. Haematological patients are among those most at risk. We evaluate here the disease course, association between comorbidities and COVID-19 severity and seroconversion potential in 50 positive patients at our clinic. Methods: We performed 1,600 diagnostic PCR nasopharyngeal swabs over a period of 8 months. We introduced a set of preventive measures so as to protect our patients and personnel. In 50 COVID-19 positive patients, we closely evaluated the course of the disease, the impact of underlying risk factors and the principal haematological diagnoses. We also evaluated the potential for seroconversion in 15 COVID-19 positive patients. Results: Strict barrier measures, especially in patients undergoing autologous stem cell transplantation, have been shown as being crucial for reducing the spread of disease.We did not record any disease outbreak and registered only one positive case during the peri-transplant period at our facility. The most common comorbidities were arterial hypertension or other cardiovascular disease, type 2 diabetes and renal impairment. Two-thirds of positive patients were on first line treatment. Hypogammaglobulinemia did not prove to be a risk factor for a severe COVID-19 course and we did not observe it to be an obstacle for seroconversion. Conclusion: Preventive measures are significant for reducing the spread of disease, especially in haematology centres. In our single centre experience, we report a mortality of 14%. Although we report a relatively small cohort and much remains yet to be clarified, our results can even now be implemented in daily practice.