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: 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.