RESUMO
Background: Rituximab-based chemoimmunotherapy regimens are backbone treatment (Tmt) for both indolent (follicular [FL], marginal zone [MZL]) and aggressive (diffuse large B-cell [DLBCL], mantle cell [MCL]) B-cell lymphomas. Standard of care (SoC) for relapsed or refractory (R/R) disease includes anti-CD20 in combination with chemotherapy and targeted therapies, such as Bruton's tyrosine kinase inhibitors (eg, ibrutinib) and phosphoinositide 3-kinase (PI3K) inhibitors. Parsaclisib is a potent and highly selective next generation PI3Kδ inhibitor that is currently being investigated in hematological malignancies. Aims: CITADEL-112 (NCT03424122) is an open-label phase 1 study evaluating the safety and tolerability of adding parsaclisib to investigator choice SoC Tmt rituximab (RIT), RIT + bendamustine (BEN), or ibrutinib (IBR) in patients (pts) with R/R B-cell lymphoma. Methods: Enrolled pts were ≥18 years and had histologically confirmed DLBCL, FL, MCL, or MZL, ECOG PS 0-2, were R/R to ≥1 (≥2 for FL) prior systemic therapy, and ineligible for stem cell transplant. Pts received parsaclisib 20 mg orally once daily (QD) for 8 weeks then 20 mg once weekly (QW) in combination with either: RIT 375 mg/m2 IV QW for 4 doses in cycle 1 (± cycle 2) (Tmt A);RIT 375 mg/m2 IV on day 1 + BEN 90 mg/m2 on day 1 and day 2 of each 28-day cycle for ≤6 cycles (Tmt B);or IBR 560 mg QD (Tmt C). Pts received treatment until disease progression, unacceptable toxicity, or withdrawal. Results: At data cutoff (May 14, 2021), 50 pts were treated (16 pts each in Tmt A and C, 18 pts in Tmt B) and 13 pts were ongoing treatment (3 pts in Tmt A, 8 pts in Tmt B, 2 pts in Tmt C). Most pts had received ≥2 prior systemic treatments (81.3%, 61.1%, and 68.8% in Tmt A [range 1-4], B [range 1-4], and C [range 1-7], respectively). The most common reasons for discontinuation were progressive disease (56.3%, 38.9%, and 50.0%) and adverse events (AEs) (12.5%, 11.1%, and 6.3% in Tmt A, B, and C, respectively). One pt in Tmt B experienced a dose-limiting toxicity of grade 4 neutropenia for >14 days. All pts experienced at least 1 treatment-emergent AE (TEAE);in Tmt A, 75.0% had grade ≥3 and 37.5% had serious TEAEs;Tmt B, 83.3% had grade ≥3 and 27.8% had serious TEAEs;and Tmt C, 62.5% had grade ≥3 and 43.8% had serious TEAEs. Common any-grade TEAEs (≥30%) included neutropenia (62.5%), diarrhea (37.5%), and anemia (31.3%) in Tmt A;neutropenia (50.0%), abdominal pain, asthenia, diarrhea, and nausea (each 33.3%) in Tmt B;neutropenia (50.0%) and increased ALT and increased AST (each 37.5%) in Tmt C. Most common grade ≥3 TEAEs (≥15%) were neutropenia (50.0%) and diarrhea (18.8%) in Tmt A, and neutropenia (38.9% and 25.0%) in Tmt B and Tmt C, respectively. Serious TEAEs occurring in >1 pt were COVID-19, diarrhea, and pneumonia (n = 2 each) in Tmt A, and atrial fibrillation (n = 2) in Tmt C. TEAEs with fatal outcome were reported in 2 pts in Tmt A (COVID-19 and COVID-19 pneumonia [n = 1], interstitial lung disease [n = 1]) and 1 pt in Tmt C (COVID-19, acute kidney injury). Parsaclisib dose interruption or dose reduction due to TEAEs occurred in 75.0% and 18.8% of pts, respectively, in Tmt A;66.7% and 27.8% of pts, respectively, in Tmt B;and 56.3% and 18.8% of pts, respectively, in Tmt C. Summary/Conclusion: Parsaclisib 20 mg QD for 8 weeks followed by 20 mg QW can be safely combined with RIT, RIT + BEN, or IBR in pts with R/R B-cell lymphomas. The tolerability profile of the combination regimens was manageable, with no unexpected safety concerns.
RESUMO
Introduction:Recently there has been a renewal of therapeutic tools for the treatment of lymphoid neoplasms to increase the antitumor efficacy and reduce the toxicity generated by conventional chemotherapies, which adds to the intrinsic immunological dysfunction of the disease itself. To date, few data are published about infection risk of these new drugs, and the need for infectious prophylaxis is unknown. The aim of the study is to analyze the infectious complications in patients with LPD treated with monoclonal antibodies (obinutuzumab, ofatumumab, brentuximab, nivolumab and pembrolizumab), BTK inhibitors (ibrutinib, acalabrutinib) and PI3K inhibitors (idelalisib). Methods: Multicenter retrospective study in patients with LPD treated with targeted therapies (single agents or combination) in 18 Hematology centers in Spain, from the time of their commercial availability to March 2020. Patients in clinical trials were excluded as well as patients with active infections at the beginning of treatment. Results:During the study period, 380 patients were included.Baseline characteristics of the entire cohort are shown in Table 1.Median follow-up was 17.3 months (range 0-103), the longest follow-up corresponding to CLL patients (24 months, range 0-98) and the shortest to LBCL (5 months, range 0-25). Median exposure to target drugs was 8 months (range 0-72).Ibrutinib was administered to 219 patients(1 FL, 147 CLL, 27 MCL, 10 DLBCL, 1 TL and 32 WM, 1 HL),Brentuximab to 49(31 HL, 14 TL and 4 DLBCL) andIdelalisibto 35 patients (16 affected by chronic lymphocytic leukemia - CLL, 15 FL and 1 DLBCL, 1 WM, 1MCL, 1HL).Obinutuzumabcombinations were used in 10 (6 CLL, 3 FL, 1 MCL) and 5 HL patients (of which 4/5 underwent previous BMT) receivedNivolumab. A total number of 237 infectious events occurred in 148/380 patients (38.9%), 39% of which were grade 3 and 54/148 (36.4%) experienced 2 or more infective episodes: of those 54, 21 (38%) had underwent 3 or more lines of therapy and 28 (51%) had hypogammaglobulinemia. Hospitalization was required in 59.2% events. A bacterial cause of infection was reported in 40% of cases, and viral in 16%, including 11/237 (4,6%) SARS-CoV-2 infection. Invasive fungal infection (IFI) occurred in 3.3% (8/237). Noteworthy, no case of PJP was identified. Lung was the most frequent site of infection in 24% of cases (57/237) while the upper respiratory tract was involved in 17% of events (41/237). Urinary tract infections were diagnosed in 10% (24/237). Other sites involved were skin and soft tissue 7%, gastrointestinal tract 5,4%, bloodstream infections 3% and catheter related infections 2,5%. Considering drugs individually, 86 patients that receivedIbrutinib(39.2 %)experienced a total of 137 infectious episodes: 30% bacterial, 19% viral, 5% fungal and 45% clinical and image-based infections;the 17(34.6%of those who received Brentuximab, experienced a total of 16 infectious episodes: 56% bacterial, 37.5% viral infections and one catheter-related sepsis. Of those who receivedIdelalisib,18 (51.4%)experienced a total of 28 episodes: 42% bacterial, 14% viral and 7% fungal. Four patients treated withObinutuzumabcombinations (40%) experienced one infection during treatment (25% bacterial and 75% viral). Only one patient treated withNivolumabexperienced more than three infections, he was also under corticosteroid treatment. Focusing on IFI (Table 2): 7/8 infections were identified in CLL patients, 6 out 7 being on ibrutinib treatment and 1/7 on Idelalisib.Aspergilluswas the fungus most frequently isolated. The targeted drug was discontinued temporarily in 4 patients and indefinitely in 3. Twenty three (6%) patients died due to infection in our series. Conclusions: 1. We identified 38.7% infections in our LPD patients treated with targeted drugs, with a median drug-exposure time of 8 months (range 0-72), with a non-negligible incidence of bacterial infections. 2. The highest rates of infection were found in patients treated with with Idelalisib and Ibrutinib (51.4% and 39.2% respectively). 3. IFI (3.3%) occurr d with low frequency, mostly in CLL patients during ibrutinib treatment, leading to its temporal discontinuation in most of the cases. 4. No case of PJP was identified in our cohort. 5. An analysis to determine risk factors for infection and the optimal monitoring and prophylaxis for these patients is ongoing. [Formula presented] Disclosures: Hernandez-Rivas:Janssen:Membership on an entity's Board of Directors or advisory committees;Abbvie:Membership on an entity's Board of Directors or advisory committees;Roche:Membership on an entity's Board of Directors or advisory committees;AstraZeneca:Membership on an entity's Board of Directors or advisory committees;Gilead:Membership on an entity's Board of Directors or advisory committees;Celgene/BMS:Membership on an entity's Board of Directors or advisory committees;Rovi:Membership on an entity's Board of Directors or advisory committees.Lopez-Guillermo:novartis:Consultancy;celgene:Consultancy, Research Funding;roche:Consultancy, Research Funding;gilead:Consultancy, Research Funding.