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Background: Chronic lymphocytic leukemia (CLL) and myelodysplastic syndromes (MDS) are two of the most frequent hematological malignancies. CLL and MDS are also considerably heterogeneous in terms of clinical course and response to treatment, ranging from relatively indolent to extremely aggressive. Thus, open issues abound regarding the impact of CLL and MDS and their treatment on patients' quality of life (QoL). Patient-reported outcomes (PROs) have been identified as an emerging paradigm, aiming to capture the patient's perspective onselfassessed health status. Obviously, these data are critical with regards to the evaluation of the treatment effects and the patients' QoL, while also enabling the positioning of the patient as a key stakeholder within the healthcare decision making process. Novel methodologies and eHealth approaches can be valuable for the adoption of the PRO paradigm in real-world settings as they can promote richer, less obtrusive and preemptive communication which could facilitate early recognition of potential symptoms of disease or treatment adverse effects (e.g., adverse drug reactions, lack of physical activity, worsening of QoL etc.). Aims: In this , we present the lessons learned thus far from the implementation of the MyPal project, a Horizon 2020 Research & Innovation Action aiming to foster palliative care for patients with CLL and MDS by leveraging the ePRO paradigm. Methods: MyPal aspires to empower patients and their caregivers to more accurately capture their symptoms/conditions, communicate them in a seamless and effective way to their healthcare providers (HCPs);and, ultimately, to foster action through advanced methods of identification of important deviations relevant to the patient's state and QoL. To this end, MyPal developed a technical platform including a mobile app for patients with CLL and MDS, collecting information via standardized questionnaires and other information sources (e.g., wearable sensors), also enabling spontaneous symptoms reporting, educational material provision, motivational messages, discussion guides, notifications etc. A data intensive web-based dashboard platform is also provided for healthcare professionals, providing real-time analytics, enabling a better view of collected PROs and other relevant information on patients' health status. Currently, a randomised clinical study is being conducted in 4 European countries to evaluate the proposed intervention and its potential impact on patients' QoL. Results: Based on this experience, a number of key issues have emerged: (a) while patients are generally positive about the use of eHealth, they are still reluctant about engaging in eHealth clinical studies;(b) digital literacy levels differ across different age groups as well as among different cultural contexts;(c) the COVID-19 pandemic seriously hindered patient recruitment due to the widely adopted recommendations for patients to avoid visits to hospitals unless absolutely necessary but (d) the COVID-19 pandemic also highlighted the potential benefits for HCPs of using eHealth tools in order to deliver patient care in a more decentralized and patient-centric fashion. Summary/Conclusion: In conclusion, MyPal is likely to provide important new evidence about how digital health systems can be used to improve QoL and facilitate better communication between patients with hematological malignancies and HCPs.
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Introduction: The CHOICE study was primarily designed to capture CLL patients' (pts) preferences towards different treatment attributes through a Discrete Choice Experiment (DCE) in Italy. This study was carried out in the period Feb-Jul 2020, during the 1st wave of COVID19 pandemic, and provides an insight of the pts' perception. about treatments available in CLL (1-2). Methods: This cross-sectional multicenter observational study enrolled, WATCH&WAIT (W&W) or TREATED CLL pts (~50% each, controlled at site level). Exclusion criteria were inability to take oral drugs, cognitive disorders that could impair questionnaire's comprehension and concomitant therapy for other malignancies. Pts were asked to fill in aDCE Questionnaire, composed of 9/10 blocks (for W&W/TREATED respectively) each composed of 8 comparisons between 2 profiles with the following attributes: treatment and relevant duration, PFS, risk of infection, risk of organ damage, risk of diarrhea (levels specified in Figure 1). Each pt was centrally assigned to 1 block of 8 comparisons. Pts could ask questionnaire explanations to the medical staff, but they were asked to self-complete it. Results: 401 pts from16 centers were enrolled in the study,199 W&W and 198 TREATED pts completed the questionnaire and were considered evaluable. Main pts' characteristics are shown in Table 1. Of the 198 TREATED pts, 73.7% were ON-treatment (30.8% 1st-line, 69.2% further lines) while 26.3% were OFF-treatment. W&W pts rated as the most attribute of treatment important the 'Possibility of infections' (relative importance, RI=36.2%), followed by 'Treatment and Relevant duration' (RI=28.0%) and 'PFS' (RI=16.9%). (Figure1A). When stratifying pts by geography, W&W pts from the North regions (more impacted during the 1st wave) rated as most important the 'Treatment and Relevant duration' (RI=40.3%) followed by the 'Possibility of infection' (RI=27.2%). Pts from the Center-South regions rated as most important the 'Possibility of infection' (RI=43.4%) followed by the 'Possible occurrence of Organ damage' (RI=21.6%). TREATED pts gave more importance to the 'Treatment and relevant duration' (RI =33.3%) followed by the 'Possibility of infections' (RI =28.8%) (Figure1B) with no difference between patients from the north and center-south areas. Conclusions: Unlike other DCE studies available in the current literature (1-2), the results of the CHOICE study may have been influenced by the pandemic. While the essential attribute in pre-pandemic DCE studies was the PFS, the most important attribute in DCE studies conducted during the first pandemic wave was represented by the infection concerns. Hospital access constraints, the necessity for personal protective equipment, and social distance may have influenced patient responses. (Table Presented).
ABSTRACT
BACKGROUND: The COVID-19 pandemic has created enormous challenges for the clinical management of patients with hematological malignancies (HMs), raising questions about the optimal care of this patient group. METHODS: This consensus manuscript aims at discussing clinical evidence and providing expert advice on statements related to the management of HMs in the COVID-19 pandemic. For this purpose, an international consortium was established including a steering committee, which prepared six working packages addressing significant clinical questions from the COVID-19 diagnosis, treatment, and mitigation strategies to specific HMs management in the pandemic. During a virtual consensus meeting, including global experts and lead by the European Society for Medical Oncology and the European Hematology Association, statements were discussed and voted upon. When a consensus could not be reached, the panel revised statements to develop consensual clinical guidance. RESULTS AND CONCLUSION: The expert panel agreed on 33 statements, reflecting a consensus, which will guide clinical decision making for patients with hematological neoplasms during the COVID-19 pandemic.
Subject(s)
COVID-19 , Hematologic Neoplasms , COVID-19 Testing , Consensus , Hematologic Neoplasms/epidemiology , Hematologic Neoplasms/therapy , Humans , PandemicsABSTRACT
Introduction: All the available CLL therapies differ for relevant aspects as duration of response, mode of administration, treatment duration and adverse events: the CHOICE study was designed to investigate CLL patients' Quality of Life (QoL) and preferences towards different treatment attributes through a Discrete Choice Experiment (DCE) in Italy. Due to the timeline of the study, started in Feb2020, the collected data offer an insight of patients' perception and attitude during the 1 st wave of the COVID-19 pandemic, as opposed to other DCE results available in CLL (1-2). Methods: This cross-sectional multi-center observational study enrolled patients (pts) with CLL, WATCH&WAIT (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 questionnaire's comprehension and concomitant therapy for other malignancies. Pts were asked to fill in 3 QoL questionnaires: EQ-5D-5L, EORTC QLQ-C30, QLQ CLL-16, described elsewhere. DCE Questionnaire was composed of 9/10 blocks (for W&W/TREATED, respectively) each composed of 8 comparisons between 2 profiles with the following attributes: “Treatment and relevant duration”, “PFS”, “Possibility of infections”, “Possible occurrence of organ damage”, “Possible occurrence of diarrhea”, with levels specified in Fig1. Each patient (pt) was centrally assigned to 1 block of 8 comparisons. Each pt could ask questionnaire explanations to the medical staff but self-completed it on an App specifically developed for the study. Results: 401 pts were enrolled in Italy across 16 centers (Feb-Jul 2020),199 W&W and 198 TREATED pts completed the DCE questionnaire and were included in the evaluable population. Main pts' characteristics are shown in Table 1. 73.7% of TREATED pts were ON-treatment (30.8% in 1st-line, 69.2% in further lines) and 26.3% were OFF-treatment. DCE results showed that W&W pts rated as most important the ‘Possibility of infections’ (relative importance, RI=36.2%), followed by ‘Treatment and Relevant duration’ (RI=28.0%), ‘PFS’ (RI=16.9%), while ‘Possible occurrence of organ damage’ (RI=12.5%) and ‘Possible occurrence of Diarrhea’ (RI=6.4%) had lower impact on the preference (Fig 1A). DCE in TREATED pts showed that they gave more importance to ‘Treatment and relevant duration’ (RI =33.3%) followed by ‘Possibility of infections’ (RI =28.8%). The RI of the other attributes was lower: ‘Possible occurrence of organ damage’ (RI =19.4%), ‘PFS’ (RI =9.8%), ‘Possible occurrence of diarrhea’ (RI =8.7%, Fig 1B). A sub-analysis stratifying pts from Northern regions (more impacted during the 1 st wave of the pandemic) and Center-Southern regions showed that in W&W pts from North Regions the attribute with a higher impact is ‘Treatment and Relevant duration’ (RI=40.3%) followed by ‘Possibility of infection’ (RI=27.2%), while in W&W pts from Central-Southern area, the attribute with a higher impact is ‘Possibility of infection’ (RI=43.4%) followed by ‘Possible occurrence of Organ damage’ (RI=21.6%). In TREATED pts no difference between the 2 groups has been shown and the results are consistent with the total population. Conclusions: CHOICE study was planned to understand CLL patients' preferences towards different treatment attributes, but the results have been impacted by the concurrent COVID-19 pandemic. In contrast to previously published DCEs (1-2), where PFS was the most important attribute, in the CHOICE study pts put much more emphasis on their concerns about possible infections: this could be due to the influence of the 1 st Covid-19 pandemic wave, with the relevant feeling of uncertainty, also due to the great attention that media has dedicated to the issue of infection in general, especially for vulnerable individuals such as CLL pts. The limitation in hospital access during the 1 st wave and the overall need of personal protection (masks usage) and s cial distancing might have influenced patients' responses too. The “infodemic” and the uncertainty had probably such a strong effect on patient's feelings, that PFS was no longer the most important attribute being substituted by the fear of hospitals access and infections. We thereby suggest that the pandemic had a great impact not only on the conduct of the study but also on patients' perception of their disease, if not properly reassured. [Formula presented] Disclosures: Molica: Astrazeneca: Honoraria;Abbvie: Consultancy, Honoraria;Janssen: Consultancy, Honoraria. Laurenti: AbbVie: Consultancy, Honoraria, Research Funding;Gilead: Honoraria;Roche: Honoraria, Research Funding;Janssen: Consultancy, Honoraria;AstraZeneca: Consultancy, Honoraria;BeiGene: Honoraria. Ghia: Gilead: Consultancy, Research Funding;Celgene/Juno/BMS: Consultancy, Honoraria;BeiGene: Consultancy, Honoraria;ArQule/MSD: Consultancy, Honoraria;AstraZeneca: Consultancy, Honoraria, Research Funding;Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding;AbbVie: Consultancy, Honoraria, Research Funding;Janssen: Consultancy, Honoraria, Research Funding;Roche: Consultancy, Honoraria;Sunesis: Research Funding. Coscia: Gilead: Honoraria;Janssen: Honoraria, Other, Research Funding;AstraZeneca: Honoraria;AbbVie: Honoraria, Other. Cuneo: AstraZeneca: Consultancy, Speakers Bureau;Janssen: Consultancy, Speakers Bureau;Gilead: Consultancy, Speakers Bureau;AbbVie: Consultancy, Speakers Bureau. Gaidano: Beigene: Honoraria;Janssen: Honoraria, Speakers Bureau;AstraZeneca: Honoraria;AbbVie: Honoraria, Speakers Bureau;Incyte: Honoraria. Mauro: Takeda: Consultancy, Speakers Bureau;Gilead: Consultancy, Research Funding, Speakers Bureau;Roche: Consultancy, Speakers Bureau;Janssen: Consultancy, Speakers Bureau;AstraZeneca: Consultancy, Speakers Bureau;AbbVie: Consultancy, Speakers Bureau. Pane: AbbVie;Amgen;Novartis: Other: Travel, accommodation, expenses;AbbVie;Amgen;Novartis, GSK, Incyte: Speakers Bureau;Novartis Pharma SAS;: Research Funding;AbbVie;Amgen;Novartis, GSK, Incyte: Consultancy. Gualberti: AbbVie: Current Employment. Iannella: AbbVie: Current Employment. Finsinger: AbbVie: Current Employment. Caira: AbbVie: Current Employment. Sportoletti: AstraZeneca: Consultancy, Honoraria;Janssen: Consultancy, Honoraria;AbbVie: Consultancy, Honoraria.
ABSTRACT
Background: Undetectable MRD (uMRD) has become an achievable endpoint for patients (pts) with CLL, in particular using the BCL2 inhibitor VEN allowing treatment discontinuation in a MRD-driven approach. uMRD can be reached in a proportion of pts with VEN mono, and in larger fraction in combination with the BTK inhibitor IBR. It remains to be established who can achieve best responses with single agent or combination strategies. Aims: This phase 2 multicenter MRD-driven Italian study aims at discontinuing treatment upon reaching uMRD in pts with relapsed/refractory CLL treated with VEN mono or through the addition of IBR in pts who did not achieve uMRD with the single agent. Methods: VEN mono (up to 400 mg/day as per label) was administered for 12 months. MRD in peripheral blood (PB) and bone marrow (BM) was evaluated using the ERIC 6-color flow panel. Pts with uMRD in both PB and BM at C12D1 discontinued VEN at C12D28. Pts with detectable MRD in PB and/or BM added IBR 420 mg/day from C13D1 and continued both drugs up to C24D28, uMRD, progression or toxicity (whichever first). After C24D28, pts with detectable MRD and still in response continued IBR alone. The primary endpoint was uMRD4 (<1 CLL cell in 104 leukocytes) in both PB and BM. Results: 38 pts (recruited from Nov 2017 to Jul 2018) started VEN. Median number of prior therapies was 1 (range 1-4), 61% were previously treated with FC+/-R;8/33 (24%) carried del(17p);10/30 (33%) TP53 mutations, and 24/30 (80%) unmutated IGHV. One pt discontinued treatment due to myelodysplasia (unrelated to VEN) and 1 pt due to COVID-19. As of 31 Jan 2021, overall response rate with VEN mono was 36/38 (95%), 19 CR and 17 PR. As per protocol, 17 pts (45%) with uMRD4 in PB and BM at C12D1 discontinued VEN at C12D28. 19 (55%) responsive cases with detectable MRD at C12D1 added IBR to VEN from C13D1. By combining IBR and VEN for a median of 7 months (range 3-10) 5/10 pts in PR improved their response to CR, 16/19 (84%) achieved uMRD4 in both PB and BM (Fig. 1), thus stopping both therapies. The remaining 3/19 continued IBR. After a median follow up of 30 months, median PFS has not been yet reached;3 pts progressed without treatment need, 1 pt restarted VEN mono as per protocol, 2 pts developed Richter transformation. 11/33 pts (33%) who discontinued treatment in uMRD, after a median observation of 30 months remain uMRD (6 treated with VEN only). No cases of clinical and/or laboratory tumor lysis syndrome were reported in 39 pts (1 excluded from the efficacy analysis because of atypical phenotype). Adverse events were mild, with no discontinuations or dose reductions;with prolonged follow-up no new relevant toxicities occurred. Summary/Conclusion: Our updated results demonstrated that a sequential MRD-guided approach is feasible and leads to an overall uMRD in 33/38 pts (87%) with either VEN mono or in combination with IBR. Interestingly, 84% of pts who did not achieve uMRD after VEN alone obtained uMRD after the addition of IBR and the remaining 3 patients who did not obtain uMRD even after the combination, could be selected for continuous IBR. Median PFS is not yet reached after 30 months of follow-up. This MRD-driven sequential approach allows to reach identical depth of response in each patient enrolled in the study using a personalized intensification avoiding unnecessary drug exposure, ultimately identifying the few pts that may benefit from continuous IBR. Time to clinical progression, response to VEN retreatment, and characteristics of pts with persistent MRD remain to be established.
ABSTRACT
The treatment of chronic lymphocytic leukemia (CLL) has been radically changed in the last years thanks to the targeted therapies, including kinase (i.e. ibrutinib) and BCL2 (i.e. venetoclax) inhibitors. Venetoclax (VEN) in particular is able to obtain undetectable minimal residual disease (uMRD), though only in a proportion of patients (pts) when given as single agent, thus warranting the need of different strategies in those not achieving uMRD. We designed a phase 2 multicenter Italian study where ibrutinib (IBR) is added to VEN based on a MRD-driven strategy aiming at obtaining uMRD and discontinuing both treatments in pts who did not achieve uMRD with VEN mono. Study treatment started with VEN (ramp up to 400 mg/day as per current label) for 12 months. MRD status in peripheral blood (PB) and bone marrow (BM) was evaluated using the 6-color flow cytometry assay recommended by ERIC (CD5/CD81/CD79b/CD19/CD43/CD20). Pts with uMRD in both PB and BM at C12D1 discontinued VEN at C12D28 and entered the follow-up phase. Pts with detectable MRD in PB and/or BM added IBR 420 mg/day starting from C13D1 and continued both drugs up to maximum C24D28, uMRD, progression or unacceptable toxicity (whichever occurs first). After C24D28, pts with detectable MRD and still in response continued IBR alone. The primary endpoint was uMRD4 (<1 CLL cell in 104 leukocytes) in both PB and BM. We report here the results as of 15Jul2020 (data cutoff). Thirty-eight pts (recruited from Nov 2017 to Jul 2018) fulfilled eligibility and started VEN. Baseline characteristics included: median number of prior therapies 1 (range 1-4) (60.6% previously treated with FCR or FC);del(17p) in 8/33 (24%);TP53 mutations in 10/30 (33%), and unmutated IGHV in 24/30 (80%). At the data cut-off, 35/38 evaluable pts still in the study have reached C24D1, 1 pt discontinued treatment due to myelodisplasia (considered unrelated to study treatment) before C12D1 and 1 pt progressed on VEN monotherapy shortly before that timepoint, 1 evaluation is still missing due to COVID-19 restrictions. At C12D1, uMRD4 in PB was achieved in 19/38 (50%) pts (Figure 1), 17/19 (89.5%) had uMRD4 confirmed in BM. Overall response rate with VEN single-agent was 36/38 (94.7%), 9 CR and 27 PR. As per protocol, the 17 pts (45%) with uMRD4 in PB and BM at C12D1 discontinued VEN at C12D28. Nineteen responsive cases with detectable MRD at C12D1 added IBR to VEN starting from C13D1. The combination of IBR and VEN led to an improved reduction of the depth of MRD in all but 3 pts with 16/19 (84%) achieving uMRD4 in both PB and BM between C16D1 (first MRD assessment after starting IBR) and C24D1, thus stopping both therapies as per protocol. After a median follow-up of 25.4 months (range 6.1-33.5) from treatment initiation, no clinical progression was observed among those discontinuing treatment in uMRD, while MRD4 relapse occurred in 21/33. Median time to MRD4 relapse in those who achieved uMRD at any timepoint and discontinued treatment was 4 months (range 2-13). Twelve pts (6 treated with VEN only) remain uMRD after stopping treatment, with a median observation of 13 months (range 3+-18+) since confirmed uMRD4. Safety data were analyzed in the intention-to-treat cohort (39 pts). No cases of clinical tumor lysis syndrome (TLS) and/or biochemical TLS were reported in the 39 pts exposed to VEN. Adverse events (AEs) were mild, with no treatment discontinuations or dose reductions. Five Serious AEs (Table 1) and 130 AEs (Table 2) occurred in 28 patients, without any SUSARs. All 5 SAEs were deemed unrelated to study drug(s) and 4/5 have resolved without sequelae. In conclusion, we here present the updated results of our study including the combination phase of VEN with IBR. This sequential MRD-guided approach was feasible and led to deeper responses in about 85% of pts not achieving uMRD4 after VEN alone. With this tailored and time-limited strategy 33 out of 38 pts (87%) obtained uMRD4 in PB and BM either after VEN monotherapy or the IBR-VEN combination, indicating we may reach identical depth of re ponse with a personalized intensification and avoid unnecessary drug exposure. Time to clinical progression and response to VEN retreatment in this cohort remain to be established as well as the biological characteristics of those pts with persistent MRD despite the combined treatment. Updated results with further sequential MRD and clinical monitoring after treatment discontinuation will be presented at the meeting. [Formula presented] Disclosures: Scarfo: Gilead: Membership on an entity's Board of Directors or advisory committees;AstraZeneca: Honoraria;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Farina: Abbvie: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees. Gaidano: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Astrazeneca: Membership on an entity's Board of Directors or advisory committees;Sunesys: Membership on an entity's Board of Directors or advisory committees. Reda: Janssen: Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees;Gilead: Membership on an entity's Board of Directors or advisory committees. Coscia: Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees;Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Karyopharm Therapeutics: Research Funding. Laurenti: Roche: Honoraria;Gilead: Honoraria;Janssen: Honoraria;AbbVie: Honoraria. Varettoni: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees;AbbVie: Other: Travel/accommodations/expenses;Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses. Ghia: Lilly: Consultancy, Honoraria;Sunesis: Consultancy, Honoraria, Research Funding;Adaptive, Dynamo: Consultancy, Honoraria;MEI: Consultancy, Honoraria;Celgene/Juno: Consultancy, Honoraria;Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding;BeiGene: Consultancy, Honoraria;Acerta/AstraZeneca: Consultancy, Honoraria;ArQule: Consultancy, Honoraria;Gilead: Consultancy, Honoraria, Research Funding;AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding;Novartis: Research Funding.