ABSTRACT
Background: Secondary antibody deficiency (SAD) is typical of hematological malignancies, such as chronic lymphocytic leukemia (CLL), multiple myeloma, and lymphoma or as a side effect of their treatment. Immunological defects are observed in 25-85% of CLL patients (pts), both naïve and previously treated, depending on duration, stage of disease, treatment, patient's age, and comorbidities. (Na et al., 2019;Patel et al., 2019;Zinzani et al., 2019;Reiser et al., 2017). In CLL pts, SAD increases the risk of infections, with overall higher morbidity and mortality Antibiotics administration and vaccinations are recommended as risk-reduction strategies. No real guidelines are available, but many indications warrant immunoglobulins replacement therapy (IgRT) in selected pts with low IgG (<5 g/l) or with more than three infective episodes per year despite antibiotic treatment and timely vaccination (Na et al., 2019;Reiser et al., 2017). No clear indications are available regarding the delivery method (intravenous or subcutaneous), dosage, frequency of administration, and duration of IgRT. Aims: The aim of this study is to assess the efficacy and the safety of SCIg on CLL patients in terms of infectious events, immune recovery and lymphocytes subset, impact on quality of life (QoL) on CLL pts in the Covid-19 era. Methods: Ten CLL pts with SAD have been treated with subcutaneous IgRT (SCIg) from October 2019 to December 2020. The median age and body weight of the pts were 66 years (56-88) and 68 kg (52-86) respectively. Five patients had comorbidities (hypertension, diabetes mellitus, and lung diseases) and 90% of them had an Eastern Cooperative Oncology Group (ECOG) performance 0-1. Five pts presented with unmutated IgVH and one of them also had 17p deletion. The median number of prior therapies was 2 (IBR, BR, Chl-antiCD20, FCR, in 5, 4, 4, 3 pts, respectively). At that time, 7 pts were on therapy (IBR, Ven, Alkylating Agent in 4, 1, 2 pts, respectively). None presented neutropenia. All pts underwent antibiotic prophylaxis with trimetroprin-cotimoxazole, sometimes associated with clarithromycin, and influenza vaccinations. The median baseline IgG level was 485mg/dl (118-817), with a median of 3 infection/year (1-5;pneumonia, UTI). Patients' characteristics are reported in Table 1. All pts received 10 g total dose hyaluronidase-free SCIg over a 1 h in double-needle subcutaneous infusion every 15 days for one year, independently from body weight. After the first dose, administered in a hospital setting to make the patient comfortable with their personal pump, the next doses were self-administered at home. The IgG level and CD4/CD8, CD19, and CD16/56 (natural killer, NK) lymphocytes subset were recorded at baseline and every three months during the observation period to monitor the immunological reconstitution as the therapy went on. Results: In our monocentric experience from October 2019 to December 2020 no patient experienced infectious events nor Covid-19 mediated interstitial pneumonia while on SCIg therapy. All patients tolerated well the therapy: nobody interrupted the treatment and only one patient presented a skin rash (grade 2). Both dosage and administration schedule have been stable over time. Dealing with humoral immunity, IgG levels arose from a median of 485 (118-817) mg/dl to a stable median value >600 mg/dl from 6 months onward. As expected, IgA and IgM values remained below normal levels. Dealing with cellular immunity, T-cells including CD4, CD8, and natural killer (NK, CD16/56) cells displayed a stable fashion until 6 months. On the other hand, the CD19 B cells values reflect both the disease status and the ongoing treatment effects. Results are reported in Table 1. Finally, we observed advantages on adherence to treatment, QoL, and costs, since pts did not need to go to the hospital with the help of a care-giver, rather they could comfortably get their SCIg at home without any assistance. Conclusion: SCIg administration in CLL pts with SAD is efficacious and safe as infectious prophylaxis, with hig er median IgG levels, thanks to both pharmacokinetic advantages and improved adherence to treatment. Especially in the Covid-19 era, the subcutaneous route is preferred to the intravenous one, because of the self-administration at home and the granted availability to the drug itself. Finally, subcutaneous administration gives advantages to the QoL and hospital expenditure.
ABSTRACT
Ibrutinib is the only once-daily Bruton's tyrosine kinase (BTK) inhibitor with significant survival benefit vs. chemo- and/or immunotherapy in multiple phase 3 studies of patients (pts) with chronic lymphocytic leukemia (CLL). It has profoundly changed the treatment landscape of CLL with the longest follow-up. However, seven years (yrs) after ibrutinib was approved in Italy by regulatory agencies for CLL treatment, available data on the patterns of care of such pts in the setting of clinical practice is limited. Herein we present the first interim analysis (IA) of EVIdeNCE (ClinicalTrials.gov Identifier: NCT03720561), a multicenter, observational clinical study designed to describe the current management of pts receiving ibrutinib in a real-world setting in Italy in terms of retention rate: the study's primary end point. Methods EVIDENCE 312 treatment-naïve (TN) 38% and relapsed/refractory (R/R) 62% pts with CLL according to the iwCLL diagnosis criteria observed at 39 Italian hematological institutions in the period between November 2018 and October 2019. Inclusion criteria were treatment with ibrutinib according to the European Summary of Product Characteristics as per routine clinical practice started within the previous 3 months. The purpose of this IA is to provide demographics and disease characteristics at baseline and a preliminary evaluation of ibrutinib retention rate after one year of follow-up, along with its safety profile. The median age of pts at the time of ibrutinib initiation was 71.0 yrs (range 41.0-89.0), with 60% ≥70 yrs, 63.2% male, and 90% with Eastern Cooperative Oncology Group (ECOG) performance 0-1. Baseline Rai stage 0-I, II, and III-IV accounted for 18.3, 29.7, and 52.1% pts, respectively. Patients in stage IV were observed in 40% of the R/R and 27% in the TN subgroup. Considering 120 pts with known mutational status, del(17p) and/or TP53 mutation were present in 50.0% of pts (TN =52.1%, R/R = 48.6%), while IGHV was unmutated in 35.0% (TN =33.3% and R/R = 36.15) and mutated in 15.0% (TN =14.6%, R/R = 15.3%). At baseline, 62.9% of pts had comorbidities and 30.6% presented with a history of cardiovascular diseases (CVDs). A CIRS score ≥6 was observed in 28.5% of pts. The median time from CLL diagnosis to the start of ibrutinib was 5.1 yrs (TN 1.75 yrs vs. R/R 7.27 yrs). At least 1 treatment-emergent adverse event (TEAE) of any grade was experienced by 70.7% of pts. Frequencies were as follows: infections (30.8%;COVID-19 infections 3.2%), arthralgia (10.8%), neutropenia (9.3%), fatigue (8.4%), diarrhea (7.7%), atrial fibrillation (7.4%;grade 3-4, 4.2%), fever (7.1%), rash (6.4%), anemia (6.1%), and hypertension (4.2%). Mild bleeding TEAEs were reported in 16.1% of pts with no major bleeding event. TEAEs were more frequent in the elderly (≥65 yrs) while no significant differences in the rate of TEAEs were recorded in TN and R/R pts (69.7 vs. 71.4%, respectively). Serious TEAEs were reported in 21.9% of pts. Overall in intention to treat (ITT), 32 deaths (10%) were observed (TN =8, R/R = 24). The most common causes of death were infections (3.5%) and progressive disease (PD) (1.9%). Permanent discontinuation was observed in 56 (18%) of the pts (TN =17.2%, R/R = 18.7%) and it mostly occurred within the first 6 months. The main causes of discontinuation were toxicity (6.1%), PD (3.8%), and death (3.5%). Temporary interruptions (≤3 months without therapy and/or dose modifications) during the whole observation period occurred in 30.3% (TN =35.3%, R/R = 27.2%) and 37.7% (TN =37.5%, R/R = 37.8%) of pts, respectively, mainly determined by toxicity and clinical judgment. Finally, in this first IA after 17.3 months (range 1.1-27.0) median follow-up, the ibrutinib retention rate (calculated as the ratio between the number of patients who retained ibrutinib treatment over the total number of patients at risk) at 1-year was 81.9% [95% confidence interval (CI), 77.2-86.1%] with no difference between TN 83.2% (95% CI, 75.2-89.4%) and R/R 81.2% pts (95% CI, 74.9-86.4%). EVIDENCE is the first realw rld study of ibrutinib use in CLL clinical practice in Italy. Ibrutinib retention rate at one-year suggests a better knowledge and expertise of hematologists in the management of ibrutinib-related toxicities that may result in an improved long-term outcome of pts with CLL.
ABSTRACT
Introduction Ibrutinib is the only once-daily Bruton's tyrosine kinase (BTK) inhibitor with significant survival benefit vs chemo- and /or immunotherapy in multiple phase 3 studies of patients (pts) with chronic lymphocytic leukemia (CLL). It has profoundly changed the treatment landscape of CLL with the longest follow-up. However, seven years (yrs) after ibrutinib was approved in Italy by regulatory agencies for CLL treatment, available data on the patterns of care of such pts in the setting of clinical practice is limited. Herein we present the first interim analysis (IA) of EVIdeNCE (ClinicalTrials.gov Identifier: NCT03720561), a multicenter, observational clinical study designed to describe the current management of pts receiving ibrutinib in real-world setting in Italy in terms of retention rate: the study's primary end point. Methods EVIDENCE 312 treatment-naïve (TN) 38% and relapsed/refractory (R/R) 62% pts with CLL according to the iwCLL diagnosis criteria observed at 39 Italian hematological institutions in the period between November 2018 and October 2019. Inclusion criteria were treatment with ibrutinib according to the European Summary of Product Characteristics as per routine clinical practice started within the previous 3 months. The purpose of this IA is to provide demographics and disease characteristics at baseline and a preliminary evaluation of ibrutinib retention rate after one year of follow-up, along with its safety profile. Results The median age of pts at the time of ibrutinib initiation was 71.0 yrs (range 41.0-89.0), with 60% ≥70 yrs, 63.2% male, and 90% with Eastern Cooperative Oncology Group (ECOG) performance 0-1. Baseline Rai stage 0-I, II, and III-IV accounted for 18.3%, 29.7% and 52.1% pts, respectively. Patients in stage IV were observed in 40% of the R/R and 27% in TN subgroup. Considering 120 pts with known mutational status, del(17p) and/or TP53 mutation were present in 50.0% of pts (TN=52.1%, R/R=48.6%), while IGHV was unmutated in 35.0% (TN=33.3% and R/R=36.15) and mutated in 15.0% (TN=14.6%, R/R=15.3%). At baseline, 62.9% of pts had comorbidities and 30.6% presented with a history of cardiovascular diseases (CVDs). A CIRS score ≥6 was observed in 28.5% of pts. The median time from CLL diagnosis to the start of ibrutinib was 5.1 yrs (TN 1.75 yrs vs R/R 7.27 yrs). At least 1 treatment-emergent adverse event (TEAE) of any grade was experienced by 70.7% of pts. Frequencies were as follows: infections (30.8%;COVID-19 infections 3.2%), arthralgia (10.8%), neutropenia (9.3%), fatigue (8.4%), diarrhea (7.7%), atrial fibrillation (7.4%;grade 3-4, 4.2%), fever (7.1%), rash (6.4%), anemia (6.1%) and hypertension (4.2%). Mild bleeding TEAEs were reported in 16.1% of pts with no major bleeding event. TEAEs were more frequent in the elderly (≥65 yrs) while no significant differences in the rate of TEAEs were recorded in TN and R/R pts (69.7% vs 71.4%, respectively). Serious TEAEs were reported in 21.9% of pts. Overall in intention to treat (ITT), 32 deaths (10%) were observed (TN=8, R/R=24). The most common causes of death were infections (3.5%) and progressive disease (PD) (1.9%). Permanent discontinuation was observed in 56 (18%) of the pts (TN=17.2%, R/R=18.7%) and it mostly occurred within the first 6 months. Main causes of discontinuation were toxicity (6.1%), PD (3.8%) or death (3.5%). Temporary interruptions (≤ 3 months without therapy and/or dose modifications) during the whole observation period occurred in 30.3% (TN=35.3%, R/R=27.2%) and 37.7% (TN=37.5%, R/R=37.8%) of pts, respectively, mainly determined by toxicity and clinical judgment. Finally, in this first IA after 17.3 months (range 1.1 - 27.0) median follow-up, the ibrutinib retention rate (calculated as the ratio between the number of patients who retained ibrutinib treatment over the total number of patients at risk) at 1-year was 81.9% [95% confidence interval (CI), 77.2% - 86.1%] with no difference between TN 83.2% (95% CI, 75.2% - 89.4%) and R/R 81.2% pts (95% CI, 74.9% - 86.4%). Conclusions EVIDENCE is the irst real-world study of ibrutinib use in CLL clinical practice in Italy. Ibrutinib retention rate at one-year suggests a better knowledge and expertise of hematologists in the management of ibrutinib-related toxicities that may result in an improved long-term outcome of pts with CLL. Disclosures: Molica: Janssen: Consultancy, Honoraria;Abbvie: Consultancy, Honoraria;Astrazeneca: Honoraria. Scarfo: Astra Zeneca: Honoraria;Abbvie: Honoraria;Janssen: Honoraria, Other: Travel grants. Murru: Abbvie: Consultancy, Honoraria, Other: travel and accommodation;Janssen: Consultancy, Honoraria. Sportoletti: AstraZeneca: Consultancy, Honoraria;Janssen: Consultancy, Honoraria;AbbVie: Consultancy, Honoraria. Frigeri: Celgene: Consultancy, Speakers Bureau;Abbvie: Speakers Bureau;Janssen: Consultancy, Speakers Bureau;Amgen: Speakers Bureau. Sanna: Janssen: Consultancy;Abbvie: Consultancy;Astra Zeneca: Consultancy. Coscia: Janssen: Honoraria, Other, Research Funding;AbbVie: Honoraria, Other;AstraZeneca: Honoraria;Gilead: Honoraria. Reda: Abbvie: Consultancy;Astra Zeneca: Consultancy;Beigene: Consultancy;Janssen: Consultancy. Tafuri: Novartis: Research Funding;Roche: Research Funding;Celgene: Research Funding. Grugnetti: Janssen: Current Employment. Magarotto: Janssen: Current Employment. Mauro: Tskeda: Consultancy, Honoraria;Gilead: Consultancy, Honoraria;Janssen: Consultancy, Honoraria, Speakers Bureau;Abbvie: Consultancy, Honoraria, Speakers Bureau;Roche: Consultancy, Honoraria;Astra Zeneca: Consultancy, Honoraria, Speakers Bureau.
ABSTRACT
Introduction Although plenty of data exists on efficacy and safety of CLL drugs, their impact on patients' Health-Related Quality of Life (HRQoL) is largely unknown (1-2). Documentation of drug safety via traditional use of adverse events (AE) in hematology is limited if not complemented with Patient-Reported Outcomes (PRO) measures (3-4). Incorporation of HRQoL PROs is now essential to better evaluate risk-benefit of new therapeutic approaches and it is also highly valued by regulatory stakeholders (5). Most PRO data currently available for CLL patients (pts) came from randomized controlled trial settings (6-7), hence limiting generalizability of findings to CLL real-life patients. CHOICE study was designed to investigate CLL patients' QoL and preference towards different treatment profiles through a Discrete Choice Experiment (DCE) methodology in Italy. Due to the timelines of the study, which started in February 2020, the related data offer an insight into patients' perception and worries during the first wave of the COVID-19 pandemic. Methods This cross sectional, multi-center, observational study included CLL patients, treatment naïve during the watch & wait period (W&W) or already TREATED (around 50% each, controlled at site level), who signed the informed consent for study participation. Exclusion criteria were inability to take oral drugs, cognitive disorders that could impair the comprehension of the questionnaires and concomitant treatment for other malignancies. Patients were asked to fill in the following HRQoL questionnaires: EQ-5D-5L, EORTC QLQ-C30 and QLQ CLL-16, as well as a DCE questionnaire, (described elsewhere). Each questionnaire was completed by the patient on a tablet - using an App specifically developed for the study. Results 401 pts were enrolled in Italy in 16 hematology centers (Feb - July 2020);199 W&W and 196 TREATED pts completed the questionnaires and were included in the evaluable population. Main patients' characteristics are shown in Table 1. 73.7% of TREATED pts were ON-treatment (30.8% were in 1st-line, 69,2% in further lines) and 26.3% were OFF-treatment;the majority of pts (55,6%) were currently treated with a target therapy (Table1). The EQ-5D-5L questionnaire showed no significant differences between groups. In both groups more than 80% of pts reported low values (1 or 2, indicating no or small impact) on all items. Median VAS was 75 for the TREATED group and 80 for the W&W group (0-100;higher scores indicate higher QoL). QLQ C-30 / CLL-16 scores had very similar results between TREATED and W&W pts suggesting a limited impact of CLL on pts QoL. The median (IQR) QoL Scale was 83.3 (67- 83) for TREATED and 83.3 (67- 92) for W&W pts (0-100;all functional scales had high scores, that represent a better level of functioning;all symptoms' scales had low values, representing a less important symptomatology or problem, Figure 1). The main symptoms reported were fatigue, insomnia, pain, and dyspnea, while the main worry was for “future health” (Figure 1). Distribution of data was statistically different between the 2 groups only for the Role functioning Scale (p=0.024) and the Social Functioning Scale (p=0.003) of QLQ-C30 and for the Infection Scale (p<0.001) of QLQ CLL-16, always with slightly but significantly better results for the W&W group. Conclusions CHOICE study helps to understand the CLL patients' mindset and feeling in the light of the COVID-19 pandemic impact on health care for this category of pts, highlighting their preferences and worries in a large cohort of pts in Italy, allowing a comparison between TREATED and W&W pts. The main limitation of the study was its cross-sectional design, which does not allow us to evaluate any change in QoL neither with respect to the impact of the pandemic, nor to the effects of the treatment, if any. CLL pts showed a good QoL, as confirmed by both EQ-5D-5L and EORTC QLQ C-30 / CLL-16 scores, with very similar results between TREATED and W&W pts (although slightly better results in the W&W vs TREATED group). The results of th present study are consistent with previous reports, and fatigue was the most reported symptom, while worry for future health was the most relevant score in CLL-16 questionnaire. Hospital accesses reduction that was detected during the pandemic might have influenced patients' response, as well as the extreme attention towards the danger of infections, and might have impacted patients' perception on future health. [Formula presented] Disclosures: Tedeschi: Beigene: Honoraria, Speakers Bureau;AstraZeneca: Honoraria, Speakers Bureau;AbbVie: Honoraria, Speakers Bureau;Janssen: Honoraria, Speakers Bureau. Gozzetti: Janssen: Honoraria;AbbVie: Honoraria. Reda: Beigene: Consultancy;Astra Zeneca: Consultancy;Abbvie: Consultancy;Janssen: Consultancy. Gualberti: AbbVie: Current Employment. Malgieri: AbbVie: Current Employment. Finsinger: AbbVie: Current Employment.
ABSTRACT
Background: Secondary antibody deficiency (SAD) is a typical manifestation of haematological malignancies such as chronic lymphocytic leukaemia (CLL), or a side effect of their treatment. Immunological defects are observed in 25-85% of CLL patients (pts) and increases the risk of infections, with overall higher morbidity and mortality. Antibiotics administration and vaccinations are recommended as risk-reduction strategies in those pts. No real guidelines are available to recommend eligibility for prophylaxis, but many indications warrant immunoglobulins replacement therapy (IgRT) in selected pts with low IgG (<5g/l) or with more than 3 infective episodes per year despite antibiotic treatment and timely vaccination. No clear indications are available regarding the delivery method (intravenous or subcutaneous), dosage, frequency of administration and duration of IgRT. Aims: The aim of this study is to assess the efficacy and safety of subcutaneous IgRT (SCIg) and its impact on quality of life (QoL) on CLL pts in Covid-19 era. Methods: Ten CLL pts, have been treated with SCIg from October 2019 to December 2020. Median age and body weight were 66 years (56-88) and 68 Kg (52-86). Comorbidities were present in 5 pts (hypertension, diabetes mellitus, lung diseases). 5 pts had unmutated IgVH and 1 had 17p deletion. The median number of prior therapies was 2 (IBR, BR, Chl-antiCD20, FCR, in 5, 4, 4, 3 pts respectively). At that time, 7 pts were on therapy (IBR, Ven, Alkylating Agent in 4, 1, 2 pts respectively). None presented neutropenia. All pts underwent antibiotic prophylaxis with trimetroprin-cotimoxazole, sometimes associated with clarithromycin, and influenza vaccinations. Median baseline IgG level was 485 mg/dl (118-817), with a media of 3 infection/year (1-5;pneumonia, UTI). All pts received 10 g total dose hyaluronidase-free SCIg over a 1h double-needle subcutaneous infusion every 15 days over one year, independently from their body weight. After the first dose, administered in a hospital setting to make the patient comfortable with their personal pump, the next doses were self-administered at home. The IgG level and CD4/CD8, CD19 and CD16/56 (natural killer, NK) lymphocytes subset were recorded both at baseline and during the observation period to monitor the immunological reconstitution as the therapy went on. Results: No patient experienced infectious events during the SCIg therapy nor Covid-19 mediated interstitial pneumonia. All patients tolerated the therapy: nobody interrupted the treatment and only one patient presented a skin rash (grade 2). Both dosage and administration schedule have been stable over time. Dealing with humoral immunity, IgG levels arose from a median of 485 mg/dl (118-817) to a stable median value >600 mg/dl from 6 months onward. About cellular immunity, T-cells including CD4 and CD8 and NK cells displayed a stable fashion until 6 months. On the other hand, the CD19 B cells values reflect both the disease status and the ongoing treatment effects. Results were in Table 1. Finally we observed advantages on both QoL and costs, since pts did not need to go to the hospital with the help of a care-giver, rather they could comfortably get their SCIg at home without any assistance. Summary/Conclusion: SCIg administration in CLL pts is safe and efficacious as infectious prophylaxis, with higher median IgG levels, thanks to its pharmacokinetic advantages and improved adherence to treatment. Especially in the Covid-19 era, the subcutaneous route is preferred to the intravenous one, because of the self-administration at home and the granted availability to the drug itself.