ABSTRACT
Background: BCR signaling mediated through Bruton's tyrosine kinase (BTK) plays a critical role in the development and maintenance of marginal zone lymphoma (MZL). BTK inhibitors have established activity in relapsed/refractory (R/R) MZL with the phase 2 study of ibrutinib demonstrating an objective response rate (ORR) of 48% (Noy et al. Blood. 2017;129:2224-2232). Zanubrutinib is a potent and highly specific next-generation BTK inhibitor designed with greater selectivity for BTK vs TEC- and EGFRfamily kinases, which are thought to be related to off-target toxicities. Therapeutic activity of zanubrutinib was established in an early-phase study (BGB-3111-AU-003) of 20 patients (pts) with R/R MZL demonstrating an ORR of 80%, with a complete response (CR) rate of 15%, and partial response (PR) rate of 65% (Tedeschi et al. EHA 2020, abstract 2804). Aims: To present initial efficacy and safety results in pts with R/R MZL enrolled in MAGNOLIA (BGB-3111-214). Methods: MAGNOLIA is a phase 2, multicenter, single-arm study of adults with R/R MZL who had received ≥1 line of therapy including ≥1 CD20-directed regimen. All were treated with zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. Use of long-term antiplatelet and anticoagulation agents was permitted. The primary end point was ORR determined by an independent review committee in accordance with the Lugano classification. Secondary end points include ORR by investigator assessment, duration of response (DOR), progression-free survival (PFS), and safety. Results: As of January 11, 2021, 68 pts were enrolled and treated. Median age was 70 years (range, 37-95), with 28% aged ≥75 years. Subtypes included extranodal (mucosa-associated lymphoid tissue;38%), nodal (38%), splenic (18%), and indeterminate (6%) MZL. Median number of prior therapies was 2 (range, 1-6) and 32% of pts had disease that was refractory to last therapy. Median duration of drug exposure was 59.1 weeks (range, 3.7-84.1). Sixty-six pts were evaluable for efficacy. At a median study follow-up of 15.5 months (range, 1.6-21.7), investigator-assessed ORR (CR + PR) was 74% (CR 24%, PR 50%, stable disease 17%). Responses were observed in all subtypes, with an ORR of 68%, 84%, 75%, and 50% in extranodal, nodal, splenic, and indeterminate subtypes, respectively. CR rate was 36% for extranodal MZL, 20% for nodal, 8% for splenic, and 25% for indeterminate subtype. Median DOR and PFS were not reached;15-month PFS was 68% and 12-month DOR was 81%. IRC review is ongoing. Twenty-eight (41%) pts discontinued treatment: 20 due to disease progression, 1 withdrew consent, 3 required prohibited medications, 4 due to adverse events (AEs;2 due to COVID-19 pneumonia, 1 due to pyrexia attributed to disease transformation, and 1 due to myocardial infarction [MI]). The most common (≥10%) treatment-emergent AEs reported were diarrhea (22%), bruising (21%), constipation (15%), pyrexia (13%), abdominal pain (12%), upper respiratory tract infection (12%), back pain (10%), and nausea (10%). Most AEs were grade 1 or 2. Neutropenia was the most common grade ≥3 AE (10%). Two pts died from COVID-19 pneumonia and 1 pt with pre-existing coronary artery disease died from MI. No fatal AEs were considered related to zanubrutinib. All-grade AEs of interest included neutropenia (13%), thrombocytopenia (13%), atrial fibrillation/flutter (3%), and hypertension (3%). No major/serious hemorrhage was reported. No AEs led to dose reductions. Summary/Conclusion: Zanubrutinib demonstrated high response rates and durable disease control with a favorable safety profile in pts with R/R MZL.
ABSTRACT
Background: Coronavirus Disease (COVID-19) could be considered as a human model of marked inflammation combined with severe hypoxia. In this setting, both erythropoiesis and iron metabolism appear to be profoundly affected by inflammatory and hypoxic stimuli, which act in the opposite direction. In patients with SARS-CoV-2 infection, Hb levels tend to be relatively high even in the context of severe disease and marked inflammation. A better understanding of erythropoiesis and iron metabolism in COVID-19 could contribute to elucidate the relationship between hypoxia and inflammation on erythropoietic control. Aims: To investigate the prevalence of anemia, the alterations of iron homeostasis,and the relationship between inflammation,hypoxia and erythropoiesis in a cohort of COVID-19 patients admitted both to medical wards and intensive care unit (ICU). Methods: We retrospectively analyzed data of 303 patients with COVID- 19 (178 subjects admitted to medical wards and 125 subjects admitted to the ICU). Biochemical parameters were collected on admission (T0), after 7 days of hospitalization (T1) and at discharge/death (T2). Results: The median age of the patients was 62 years (53-71) and 72% were males. ICU patients had lower mean Hb levels compared to non- ICU patients (11.3±1.8 vs 12.8±1.8 g/dL at T0, 10.2±1.6 vs 12.2±1.9 g/ dL at T1, 10±1.4 vs 12±1.7 g/dL at T2;p<0.001). Mean Hb concentration did not fall under 12 g/dl in the non-ICU group and under 10 g/ dl in the ICU group during hospitalization. Hb decreased by approximately 1 g/dl in both cohorts during the first 7 days of hospitalization, then remained stable until discharge. ICU patients also showed increased inflammatory markers and ferritin levels (1401 vs 839 mcg/l at T0, p<0.001;913 vs 832 mcg/L at T1, p ns;764 vs 651 mcg/L at T2, p ns). There were no significant differences in other iron parameters between groups. Hypoxia was a prominent feature of ICU patients (P/F ratio 91 vs 224, p<0.001). Patients who were anemic on admission maintained relatively constant Hb concentrations from T0 to T2 (10.8 g/dL at T0, 10.2 g/dL at T1 and 10.4 g/dL at T2), thus remaining in a range of mild to moderate anemia. Conversely, the non-anemic group displayed a greater reduction of Hb levels (13.7 g/dl at T0, 12.7 g/dl at T1, 12 g/dl at T2). Anemic subjects were more hypoxic than non-anemic patients (P/F 151 vs 292 at T0, p<0.001) and showed significantly higher levels of CRP (10.8 vs 6.6 mg/dL), IL-6 (60.3 vs 47.7 ng/L) and leukocyte count (7290 vs 6130 x109/L). Ferritin was higher in anemic patients at T0 and T1 (1220 vs 926 mcg/L and 852 vs 896 mcg/L, p ns), decreasing more at T2 (655 vs 763 mcg/L, p ns). Median hepcidin levels, which were available for a limited subset of non- ICU patients, were elevated during the whole period: 233 ng/mL at T0, 95 ng/mL at T1 and 60 ng/mL at T2. Summary/Conclusion: In patients with SARS-CoV-2 infection, two main factors influence erythropoiesis and iron homeostasis: systemic inflammation and profound hypoxia. Markedly high ferritin and hepcidin levels reflect a strong inflammatory response. However, COVID-19 patients tend to have disproportionately high Hb levels in the contest of the inflammatory milieu. The absolute reduction in Hb levels is more prominent in patients who displayed normal Hb on admission. Conversely, anemic and profoundly hypoxic subjects show constant mean Hb levels over time. Thus, we can hypothesize that the erythropoietic drive provided by hypoxia could counterbalance the effect of inflammation on hepcidin regulation, preventing Hb levels from falling dramatically during hospitalization.
ABSTRACT
Background: Data on SARS-CoV-2 infection in Hemoglobinopathies are still scarce and controversial. Since March 2020, we, as Italian Society for Thalassemia and Hemoglobinopathies (SITE), recommended close monitoring and set up an Italian survey to verify the impact of SARSCoV- 2 infection on patients with Hemoglobinopathies (EMO AER COVID-19 NCT04746066) among Italian Centers. Aims: To explore the hypothesis of an increased vulnerability of Hemoglobinopathies to SARS-COV2 infection. Methods: After SITE proposal and Ethics Committee approval, each participating Center entered data on a specific electronic Case Report Form (eCRF) (https://covid19.site-italia.org). Inclusion criteria included positive swab or serology and at least 15 days of follow-up from either the onset of symptoms or SARS-CoV2 positivity. This cut-off is updated to February 15, 2021. Results: Twenty-seven Centers that provide care to 6121 patients with Hemoglobinopathy (65% of the Italian population) recorded a total of 275 SARS-CoV2 infections (overall, prevalence 4.5%), in 191 transfusion- dependent thalassemia cases (TDT, prevalence 5.8%), 36 non-transfusion- dependent thalassemia (NTDT, prevalence 2.3%) and 48 sickle cell disease patients (SCD, prevalence 3.7%). Median age was 41 years (IQR: 30-48, range: 9 months-85 year). Twenty-eight patients (10 %) were pediatrics (median age: 6.5 years, IQR: 4-11). Most patients (72%) had comorbidities;134 (49%) had splenectomy or functional asplenia. We observed a broad spectrum of disease severity, ranging from no symptoms in 65 patients (24%) to multisystem organ failure and death in 5 patients: 2 TDT (age: 49 and 56 years), 1 NTDT (age: 45 years), 2 SCD (age: 57 years both). Overall, 56 (20%) patients required hospitalization, 12 in high-intensity care unit;10 required support by oxygen, 11 needed more intensive ventilation support with continuous positive airway pressure (CPAP), and 7 required intubation. Nine patients required ad hoc transfusion or more than scheduled. Two SCD patients of 9 and 20 months of age, respectively, recovered after a long and life-treating disease. One TDT patient experienced reinfection after 3 months from the first;one 30w-pregnant SCD woman developed COVID-19 without consequences for herself and the fetus. Overall clinical severity has been higher in SCD than in thalassemia patients. Summary/Conclusion: The prevalence of COVID-19 in Hemoglobinopathies apparently overlaps the general population (4.5% vs 4.6%), however, these patients are more strictly observed and we could postulate that the precautions suggested or self-applied by the patients were effective. The overall mortality is 1.8% vs 3.4% and the difference may be due to the younger age of patients with Hemoglobinopathies. Our data confirm the higher risk of severe disease and death in SCD.