First-line Chronic Lymphocytic Leukemia Research Articles

Prognostic impact of genetic abnormalities in 536 first-line chronic lymphocytic leukaemia patients without 17p deletion treated with chemoimmunotherapy in two prospective trials: Focus on IGHV-mutated subgroups (a FILO study).

The potential prognostic influence of genetic aberrations on chronic lymphocytic leukaemia (CLL) can vary based on various factors, such as the immunoglobulin heavy variable (IGHV) status. We conducted an integrative analysis on genetic abnormalities identified through cytogenetics and targeted next-generation sequencing in 536 CLL patients receiving first-line chemo(immuno)therapies (CIT) as part of two prospective trials. We evaluated the prognostic implications of the main abnormalities, with specific attention to their relative impact according to IGHV status. In the entire cohort, unmutated (UM)-IGHV, complex karyotype, del(11q) and ATM mutations correlated significantly with shorter progression-free survival (PFS). Focusing on the subset of mutated IGHV (M-IGHV) patients, univariate analysis showed that complex karyotype, del(11q), SF3B1 and SAMHD1 mutations were associated with significant lower PFS. The prognostic influence varied based on the patient's IGHV status, as these abnormalities did not affect outcomes in the UM-IGHV subgroup. TP53 mutations had no significant impact on outcomes in the M-IGHV subgroup. Our findings highlight the diverse prognostic influence of genetic aberrations depending on the IGHV status in symptomatic CLL patients receiving first-line CIT. The prognosis of gene mutations and cytogenetic abnormalities needs to be investigated with a compartmentalized methodology, taking into account the IGVH status of patients receiving first-line BTK and/or BCL2 inhibitors.

Эффективность ибрутиниба в первой линии терапии у пациентов из группы высокого риска и во второй, третьей линиях при резистентном течении хронического лимфоцитарного лейкоза

Risk stratification appears to be the most valid criterion in decision-making regarding optimal specific therapy in chronic lymphocytic leukemia (CLL). The CLL International Prognostic Index takes account of unfavorable cytogenetic abnormalities (del(17p)/del(11q) and/or TP53 gene mutations) as well as the mutation status of immunoglobulin heavy chain variable (IGHV) region genes. Unmutated V(H)-status is commonly associated with such prognostically unfavorable genetic markers as del(17p)/del(11q), trisomy 12, and TP53 mutation. The combination of unmutated V(H)-status with unfavorable karyotype abnormalities (del(17p)/del(11q)) negatively affects the prognosis and overall survival rate. Besides, in high-risk CLL, the efficacy of therapy is rather low, and the development of refractoriness is possible. Targeted therapy (Bruton tyrosine kinase inhibitors) both in first line and in resistant CLL considerably increases the probability of achieving long-term remission. The present paper provides the comparative analysis of clinical and hematological efficacy and tolerability of ibrutinib in first-line CLL therapy of high-risk patients as well as second- and third-line therapies of resistant CLL. Ibrutinib shows high efficacy and low toxicity. First-line ibrutinib treatment results in a faster response and effectively reduces the probability of CLL progression. Second- and third-line ibrutinib treatment allows to overcome CLL resistance without impairing patients’ quality of life.

A Phase 2 Study of Minimal Residual Disease (MRD)-Adapted Front Line Venetoclax and Obinutuzumab in Fit Patients with Chronic Lymphocytic Leukemia (CLL): Effect of Obinutuzumab on Tumor Lysis Syndrome (TLS) Risk and Safety of Outpatient Venetoclax Dose Escalation

Introduction: Venetoclax (V) / Obinutuzumab (O) is an effective one-year fixed duration therapy for patients (pts) requiring first-line CLL treatment (tx). In CLL14, tumor lysis syndrome (TLS) risk assessment (including lymph node measurements by imaging and ALC) was required once prior to tx initiation, and O's impact on TLS risk prior to introduction of V was not a pre-planned study endpoint. Therefore, TLS prophylaxis (ppx) and tx setting for V dose escalation did not account for the possibility that O may decrease TLS risk prior to V escalation. Based on this approach, 22% of pts in the CLL14 study were high risk for TLS, thus requiring hospitalization for intensive laboratory monitoring during V dose escalation. (Fischer, NEJM 2019) We hypothesized that cycle (C) 1 of O would significantly decrease TLS risk prior to V escalation and that all pts, regardless of TLS risk category, could safely undergo a standard 5-week V dose escalation in the outpatient setting. Methods: We are conducting a Phase 2 study (NCT04447768) designed to examine the efficacy of a minimal residual disease (MRD)-adapted approach to V/O combination for fit pts in the front-line setting (study schema, Figure 1). A planned secondary study endpoint is to evaluate the effect of O monotherapy in C1 on TLS risk. Here we present interim results of TLS risk modification for the first 80 patients. Per protocol, TLS risk assessment including CT imaging and ALC measurement was performed at two defined timepoints: (1) prior to C1 day (D) 1 and (2) immediately prior to V initiation on C1D22. Key eligibility criteria: adult pts with CLL requiring first line tx per iwCLL guidelines, CIRS score ≤ 6, adequate heme function (Hgb ≥8 g/dL, ANC ≥1 x 10 9/L, Plt ≥30 x 10 9/L), creatinine clearance >50 mL/min. O was administered on C1 D1/2, 8 and 15. Per protocol, pts underwent V dose escalation in the outpatient setting, regardless of TLS risk. For pts with low and medium (med) tumor burden, TLS ppx was per FDA label. For pts who remained high TLS risk at the time of V initiation, TLS ppx throughout dose escalation included allopurinol to start at least 3 days prior to V initiation, sevelamer to start 12 hours prior to V initiation, and oral intake of ≥2 L water daily. On days of dose escalation, ppx additionally included kayexalate, rasburicase, and IV normal saline on D1 and D2 of each dose escalation. TLS labs were monitored according to FDA label guidance. Statistical analysis of TLS risk and adverse events was descriptive. Results: As of 5/2023, 80 pts have enrolled in this study. Seventy-eight pts completed the 5-week V ramp-up. Two pts were removed after receiving at least one dose of O but before repeat assessment of TLS risk and initiation of V (1 death unrelated to tx/disease, 1 patient with recurrent grade 3 (G3) O infusion-related reaction (IRR) leading to consent withdrawal). Median pt age was 57.5 years, 68% male, 95% white. Prior to tx initiation, TLS risk categories were low: 16%, med: 58%, and high: 26% (n=80). Change in TLS risk from baseline to C1D22 is detailed in Figure 2. Of the 20 pts who had sequential assessments with high baseline TLS risk, TLS risk after C1 O (C1D22) was low: 55%, med: 35%, high: 10%. For pts with med TLS risk at baseline with sequential assessments (n=45), TLS risk at C1D22 was low: 82%, med: 18%. One patient developed laboratory TLS on C1D3 following administration of O; no clinical TLS was observed. All pts accomplished V dose escalation in the outpatient setting with no observed laboratory or clinical TLS as defined by Howard Criteria. Grade 3 / 4 tx emergent AEs that occurred in >5% between C1D1 and C3D1 included neutropenia (35% G3, 11% G4), IRR (11% G3, 0% G4), and thrombocytopenia (9% G3, 3% G4). Conclusions: A single cycle of O effectively reduced TLS risk prior to introduction of V escalation with most pts achieving low or med TLS risk by C1D22. Notably, 90% of pts with high pre-tx TLS risk converted to low or med risk following C1 of O allowing for outpatient V escalation per FDA label. Further, we demonstrate that V dose escalation can be safely accomplished in the outpatient setting with close monitoring regardless of TLS risk. With this strategy, we observed no laboratory or clinical TLS during V dose escalation. Eliminating the need for hospitalization during V dose escalation may enhance patient and provider convenience and decrease the economic burden of this regimen. This study is ongoing; efficacy results of this MRD-guided approach to V/O are forthcoming.

Understanding Patient and Physician Perceptions Regarding Treatment-Related Adverse Events in First-Line Chronic Lymphocytic Leukemia (CLL)

Background Chronic Lymphocytic Leukemia (CLL) patients have various treatment options which are all associated with different adverse events. A limited number of studies have explored how patients and physicians perceive these adverse events in the frontline treatment setting. Understanding the similarities and differences in perceptions between physicians and CLL patients is an important factor in supporting shared decision-making. Aims The objective of this multi-country study was to understand the differences in patients' and physicians' perception on treatment-related adverse events in CLL. Methods CLL patients and physicians managing CLL (oncologists, hematologist-oncologists, and hematologists) were invited to complete an online survey. Participants were recruited from the US, UK, Germany, France, and Australia. The survey included a best-worst scaling (BWS) exercise to assess how ‘bothersome’ 14 potential adverse events associated with 1L CLL treatments were perceived. In a series of 18 BWS choice tasks, participants chose which was most ‘bothersome’ and which was ‘least bothersome’ among subsets of 4 adverse events. A hierarchical Bayesian (HB) model was used to estimate BWS scores for each treatment-related adverse event: BWS scores sum to 100 for each participant and a higher score indicates that an adverse event is relatively more ‘bothersome’. Results The study included 192 patients and 259 physicians. The top four most bothersome adverse events were the same for both patients and physicians, however, these were ranked in a different order (Table 1). Physicians ranked the ‘risk of cardiac events/atrial fibrillation/flutter that may require medical treatment and/or hospitalization’ and ‘risk of bleeding (hemorrhage) that requires medical intervention and/or hospitalization’ as their 2 most bothersome adverse events while patients ranked ‘Risk of infection, such as pneumonia or blood infections (sepsis) requiring medical intervention and/or hospitalization’ and ‘Risk of tumor lysis syndrome (TLS) which requires hospitalization’ as their 2 most bothersome adverse events (Table 1). The 2 least bothersome adverse events for both physicians and patients were ‘Risk of mild-to-moderate muscle, joint or bone pain (mild-to-moderate pain not interfering with daily activities) that might go away with medication’ and ‘Risk of mild-to-moderate headache (not limiting daily activities or limiting only instrumental activities such as cooking, cleaning, transportation, laundry, etc.) that might go away with medication’ (Table 1). Among patients who had experienced an adverse event (N=111), 62 (56%) reported that it had impacted their quality of life. These patients rated the following adverse events as more bothersome compared to those who had not experienced adverse events impacting quality of life: ‘risk of infection, such as pneumonia or blood infections requiring medical intervention and/or hospitalization’ (BWS scores=13.88 vs. 11.79) and ‘a side effect resulting in stopping the medication’ (9.46 vs. 6.00). These patients also rated the following adverse events as least bothersome: ‘risk of severe headache that might lead to hospitalization’ (9.55 vs. 11.68), ‘risk of severe vomiting that might lead to hospitalization’ (8.97 vs. 10.70), and ‘risk of severe muscle joint or bone pain’ (7.32 vs. 10.59), compared to those not experiencing adverse events impacting quality of life. Conclusions Patients' and physicians' perceptions were generally aligned on what adverse events related to 1L CLL treatments are most and least bothersome. However, the rank-ordering of the most bothersome adverse events varied between patients and physicians: patients were more concerned about a risk of infection or tumor lysis syndrome whereas physicians thought that a risk of cardiac event and the risk of bleeding were the most bothersome adverse events. Patients expressed hardly any concern about a risk of mild-to-moderate headache that could be resolved with medication. Interestingly, patients who had experienced a prior adverse event had differing results to patients who had not. These results should further inform and facilitate conversations between physicians and patients and improve shared decision-making when selecting a 1L regimen to treat CLL.

Combined Ibrutinib and Venetoclax for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): 5-Year Follow-up Data

Background: Ibrutinib (IBR) and venetoclax (VEN) combination is an effective therapy for patients (pts) with CLL. We previously reported results of the first-line cohort of a phase II trial of combined IBR and VEN for high-risk pts with CLL (Jain, NEJM 2019, JAMA Oncology 2021). Here we report updated data for 120 pts (80 pts in the original published cohort and 40 pts in an expansion cohort) with a median follow-up of 61.5 months. Methods: Pts with previously untreated CLL meeting IWCLL treatment criteria were enrolled. All pts had at least one high-risk feature: del(17p), mutated TP53, del(11q), unmutated IGHV, or age ≥65 years. Pts received IBR 420 mg daily for 3 cycles followed by addition of VEN (weekly dose-escalation to 400mg daily). Combined therapy was given for 24 cycles (28 days/cycle). Pts with bone marrow (BM) undetectable MRD (U-MRD) (flow cytometry; sensitivity 10 -4) at 24 cycles of combined therapy discontinued both VEN and IBR; MRD+ pts continued IBR. A trial amendment allowed an additional 12 cycles of combined VEN and IBR for pts who remained BM MRD+ after Cycle 24. Response assessments included BM and CT studies (2008 IWCLL criteria). U-MRD was defined as <0.01%; low MRD+ 0.01% to <1%; high MRD+ ≥1%. Progression-free survival (PFS) was assessed as the time from the start of study drug to CLL progression, Richter transformation, or death from any cause. Blood MRD was monitored every 6 months after active therapy. Results: Between August 2016 and February 2019, a total of 120 pts were enrolled. Median age was 64.5 years (range, 26-88 years). 86% had IGHV-unmutated CLL. 23% had del(17p)/ TP53 mutation. The median follow-up is 61.5 months. Six pts came off study during 1 st 3 cycles of IBR monotherapy; 114 pts initiated VEN. After 12 cycles of the combination, 62/120 (52%) achieved BM U-MRD remission; 43/120 (36%) were BM MRD-positive (low MRD+, n=35; high MRD+, n=8). After 24 cycles of the combination, 77/120 (64%) achieved BM U-MRD remission; 24/120 (20%) were BM MRD+ (low MRD+, n=23; high MRD+, n=1). Overall, 86/120 (72%) achieved BM U-MRD as the best response. One pt had DLBCL transformation and 1 pt had CLL progression during the first 2 year of therapy (details below). The 5-year PFS is 90.1% and 5-year OS is 95.6% (Figure 1). The 5-year PFS for pts with del(17p)/ TP53 mutation (n=27) is 86.1%. Of the 77 pts who were BM U-MRD at the end of cycle 24 of the combination, 73 discontinued all therapy, 4 pts continued IBR per treating physician discretion. Among these 77 pts, with a median follow-up of 40 months post Cycle 24, 22 pts had recurrence of blood MRD (defined as MRD ≥0.01% in 2 consecutive visits). Of the 22 pts with MRD recurrence, 5 pt had CLL progression at a median of 18 months (range, 6-30 months) from MRD recurrence (details below); 16 are being monitored without any active therapy for CLL and without clinical disease progression; 1 pt died from mesothelioma. Among the 55 pts who remain in blood U-MRD remission, 53 remain in long-term follow-up in U-MRD remission; 1 pt had B-PLL transformation and 1 patient died (found unresponsive at home; was off therapy for 2 years). There were 24 pts who were BM MRD+ at the end of cycle 24 of the combination (low MRD+, n=23; high MRD+, n=1). The only pt with high-MRD+ at end of cycle 24 was noted to have Richter transformation at that time. The remaining 23 pts (all low MRD+ in BM, range 0.01-0.95%) continued IBR monotherapy. With a trial amendment, MRD+ pts after Cycle 24 could get 12 additional cycles of VEN; 18/23 pts have resumed VEN. 11/18 (61%) pts achieved U-MRD remission during the third year of combined therapy. Only 2/23 pts are still receiving IBR (remaining pts have d/c IBR; all pts have d/c venetoclax); none of these 23 pts had clinical relapse. A total of 6 pts had CLL progression (1 during the first 2 yr of therapy; remaining 5 during off-therapy phase). 3/6 had evaluation of BTK, PLGG2 and BCL2 mutations at the time of relapse and none were detected. 5 pts have started subsequent therapy (acalabrutinib, n=4; ibrutinib, n=1; all are clinically responding); 1 pt has not yet started therapy. Conclusions: We report long term follow-up of combined IBR and VEN in first-line CLL (n=120) with a 5-year PFS of 90.1%. The 5-year PFS for pts with del(17p)/ TP53 mutation is 86.1%. Retreatment with BTK inhibitor appears effective for pts with disease relapse.

Outcomes and Treatment Sequences of Therapies with BCL2- and BTK Inhibitors in Chronic Lymphocytic Leukemia (CLL): An Analysis of Patient Data within the German CLL Study Group (GCLLSG) Registry

Introduction: Targeted agents, in particular BCL2-inhibitors (BCL2i) and BTK-inhibitors (BTKi), have profoundly improved the outcome of patients (pts) with chronic lymphocytic leukemia (CLL) and are considered standard treatment. However, the transition from treatments evaluated within clinical trials into routine clinical practice can be complex. We here present real-world data from the German CLL Study Group (GCLLSG) registry and report outcomes and treatment sequences of pts treated with either BCL2i (venetoclax) or BTKi (acalabrutinib, ibrutinib, spebrutinib, tirabrutinib, or zanubrutinib) as first administered targeted agent. Methods: Pts from multiple German sites with confirmed diagnosis of CLL and with at least one documented first-line CLL treatment between July 1 st 2014 and January 30 th 2023 were included in this analysis. Pts participating in an active clinical trial were excluded. Treatments were categorized according to the backbone of therapy and pts were allocated to either the venetoclax (Ven) or the BTKi cohort depending on their first treatment with one of these substances. Time to next treatment (TTNT), event-free survival (EFS) and overall survival (OS) were analyzed using Kaplan-Meier methods. Results: A total of 274 pts were treated with a Ven-based regimen while 915 pts were treated with a BTKi as first therapy. Median observation time from the first documented treatment (irrespective if given as first-line or in a later therapy line) was 26 months (range 0 - 296) in the Ven cohort and 78 months (range 0-266) in the BTKi cohort. For the Ven cohort, median age at the time of first Ven treatment was 71 years (range 32 - 87) with 172 pts (62.8%) being male. Median CIRS score was 2 (range 0-13) and 12 pts (7.5%) had an ECOG performance status > 1. Among 57 pts with known molecular genetics, 32 pts (56.1%) had an unmutated IGHV status and 9 out of 51 evaluable pts (17.6%) had a deletion and/or mutation TP53. Applying the CLL-IPI, 11 out of 58 evaluable pts (19.0%) were in the very high-risk group. In the BTKi cohort, median age at time of first BTKi treatment was 72 (range 32 - 92), with 628 pts (68.6%) being male. Median CIRS score was 3 (range 0-17) and 45 pts (9.5%) had an ECOG performance status > 1. Among 162 pts with available data, 108 pts (66.7%) had an unmutated IGHV status and 59 out of 130 evaluable pts (45.4%) had a deletion and/or mutation TP53. Using the CLL-IPI, 46 out of 145 evaluable pts (31.7%) were in the very high-risk group. A total of 152 of 274 pts (55.5%) in the Ven cohort received Ven as first-line treatment (median number of prior treatments: 0, range 0-9) and 352 of 915 pts (38.5%) in the BTKi cohort received a BTKi as first-line treatment (median number of prior treatments: 1, range 0-12). Among all 222 administered treatments prior to first Ven and 1090 treatments administered prior to first BTKi, chemoimmunotherapy (70.3% and 68.3%, respectively) and chemotherapy (10.4% and 17.8%, respectively) were the most frequent. For subsequent therapy following the first documented Ven or BTKi treatment, most pts were treated with targeted agent regimens. In the Ven cohort, 37 subsequent treatments were documented in 26 pts, of which 10 (27.0%) were a Ven-containing regimen and 13 (35.1%) a BTKi-containing regimen. Within the BTKi cohort, 393 subsequent treatments were administered in 264 pts, of which 146 (37.2%) included Ven and 106 (27.0%) a BTKi Treatment sequences were visualized with a sankey-diagram ( Figure 1). Median EFS from the start of the first documented Ven treatment was 31.8 months, with an estimated 2-year EFS rate of 66.6%. Median TTNT was 63.7 months and median OS was 96.5 months with an estimated 2-year OS rate of 89.5%. When Ven was given as first-line treatment, the estimated 2-year OS rate was 93.6% versus 86.5% when given in a later therapy line for the first time. For the BTKi cohort, median EFS from start of first documented BTKi treatment was 23.2 months, with an estimated 2-year EFS rate of 48.6%. Median TTNT was 68.4 months and median OS was 85.9 months with an estimated 2-year OS rate of 84.9%. When BTKi were given as first-line treatment, the estimated 2-year OS rate was 92.3% versus 81.3% when given in a later therapy line for the first time. Conclusion: EFS, TTNT and OS were comparable following Ven versus BTKi-based therapy in pts documented in the GCLLSG registry between 2014 and 2023.

Combined Ibrutinib and Venetoclax for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): 4-Year Follow-up Data

Background: Ibrutinib (IBR) and venetoclax (VEN) combination is an effective therapy for patients (pts) with CLL. We previously reported results of the first-line cohort of a phase II trial of combined IBR and VEN for high-risk pts with CLL (Jain, NEJM 2019, JAMA Oncology 2021). Here we report updated data for 120 pts (80 pts in the original published cohort and 40 pts in an expansion cohort) with a median follow-up of 4 years. Methods: Pts with previously untreated CLL meeting IWCLL treatment criteria were enrolled. All pts had at least one high-risk feature: del(17p), mutated TP53, del(11q), unmutated IGHV, or age ≥65 years. Pts received IBR 420 mg daily for 3 cycles followed by addition of VEN (weekly dose-escalation to 400mg daily). Combined therapy was given for 24 cycles (28 days/cycle). Pts with bone marrow (BM) undetectable MRD (U-MRD) (flow cytometry; sensitivity 10-4) at 24 cycles of combined therapy discontinued both VEN and IBR; MRD+ pts continued IBR. A trial amendment allowed an additional 12 cycles of combined VEN and IBR for pts who remained BM MRD+ after Cycle 24. Response assessments included BM and CT studies (2008 IWCLL criteria). U-MRD was defined as <0.01%; low MRD+ 0.01% to <1%; high MRD+ ≥1%. Progression-free survival (PFS) was assessed as the time from the start of study drug to CLL progression, Richter transformation, or death from any cause. Blood MRD was monitored every 6 months after active therapy. Results: Between August 2016 and February 2019, a total of 120 pts were enrolled. Baseline characteristics are shown in Table 1. The median follow-up is 48.8 months. Six pts came off study during 1st 3 cycles of IBR monotherapy; 114 pts initiated VEN. After 12 cycles of the combination, 62/120 (52%) achieved BM U-MRD remission; 43/120 (36%) were BM MRD-positive (low MRD+, n=35; high MRD+, n=8). After 24 cycles of the combination, 77/120 (64%) achieved BM U-MRD remission; 24/120 (20%) were BM MRD+ (low MRD+, n=23; high MRD+, n=1). Overall, 86/120 (72%) achieved BM U-MRD as the best response. We evaluated baseline pt and disease characteristics (age, gender, IGHV mutation status, CLL FISH panel, complex karyotype, TP53 mutation, del(17p)/TP53 mutation) and rate of bone marrow U-MRD at 6 months, 12 months and at any time during the combined IBR+VEN treatment. At 6 months of combined therapy, presence of TP53 mutation was associated with a lower rate of bone marrow U-MRD (p=0.03); however, none of the aforementioned characteristics, including TP53 mutation were associated with marrow U-MRD responses at 12 months or with best MRD response at any time during the combined therapy. There was a trend towards lower U-MRD rate among pts with mutated IGHV vs. unmutated IGHV at 12 month (p=0.09) and as best response (p=0.09). The 4-year PFS is 94.5% (95% CI, 90.3%-98.9%) and 4-year OS is 96.6% (95% CI, 93.3%-99.9%). The 4-year PFS by TP53 aberrant status is shown in Figure 1. The 4-year PFS for pts with del(17p)/TP53 mutation (n=27) is 90.9% and for pts without del(17p)/TP53 mutation (n=93) is 95.5%. None of the aforementioned pt/disease characteristics were associated with PFS. Of the 77 pts who were BM U-MRD at the end of cycle 24 of the combination, 73 discontinued all therapy, 4 pts continued IBR per treating physician discretion. Among these 77 pts, with a median time of 23.9 months post Cycle 24, 11 pts had recurrence of blood MRD (defined as MRD ≥0.01% in 2 consecutive visits). Of the 11 pts with MRD recurrence, 10 are being monitored without any active therapy for CLL and without clinical disease progression; 1 pt had disease progression after 22 months of treatment-free interval and is currently receiving acalabrutinib. There were 24 pts who were BM MRD+ at the end of cycle 24 of the combination (low MRD+, n=23; high MRD+, n=1). The only pt with high-MRD+ at end of cycle 24 was noted to have Richter transformation at that time. The remaining 23 pts (all low MRD+ in BM, range 0.01-0.95%) continued IBR monotherapy. With a recent trial amendment, MRD+ pts after Cycle 24 could get 12 additional cycles of VEN; 18/23 pts have resumed VEN. 11/18 (61%) pts achieved U-MRD remission during the third year of combined therapy. Conclusions: We report long term follow-up of combined IBR and VEN in first-line CLL (n=120) with a 4-year PFS of 94.5%. MRD responses and PFS were independent of baseline pt/disease characteristics. Continuation of combined therapy among marrow MRD+ pts during the second and the third year led to achievement of U-MRD in a subset of pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Obinutuzumab in the treatment of B-cell malignancies: a comprehensive review.

The type II anti-CD20 antibody obinutuzumab has structural and mechanistic features that distinguish it from the first anti-CD20 antibody, rituximab, which have translated into improved efficacy in phase III trials in indolent non-Hodgkin lymphoma and chronic lymphocytic leukemia (CLL). These gains have been shown through improvements in, and/or increased durability of, tumor response, and increases in progression-free survival in patients with CLL or follicular lymphoma (FL). Ongoing research is focusing on the use of biomarkers and the development of chemotherapy-free regimens involving obinutuzumab. phase II trials of such treatment regimens have shown promise for CLL, FL and mantle cell lymphoma, while phase III trials have highlighted obinutuzumab as the antibody partner of choice for novel agents in first-line CLL treatment.

P1713: VENETOCLAX IN COMBINATION WITH OBINUTUZUMAB IN FIRST LINE CHRONIC LYMPHOCYTIC LEUKEMIA IN ARGENTINA: A COST-EFFECTIVENESS ANALYSIS

Background: The efficacy of venetoclax plus obinutuzumab (VenG) was examined in the CLL14 clinical trial, in unfit Chronic Lymphocytic Leukemia (CLL) patients who have not been previously treated. Aims: The aim of the study was to estimate the cost-effectiveness of VenG in the treatment of first-line unfit CLL patients in Argentina Methods: A three-state partitioned-survival model (with health states of progression-free survival (PFS), post-progression survival (PPS) and death), developed in accordance with NICE and ISPOR decision modelling guidelines, was adapted to Argentina setting and was used to estimate the accumulated costs and outcomes in terms of life years (LY) and quality-adjusted life years (QALY). A 30-year time horizon and the Social Security’s payer’s perspective were assumed. Cost-effectiveness was estimated by comparing a 12-month fixed duration of VenG versus (vs.) chlorambucil-obinutuzumab (ClbG) based on the CLL14 clinical trial. Other comparators included treat-to-progression therapies, such as ibrutinib (IBR), and a 6-month course of bendamustine + rituximab (BR). Using a network meta-analysis, the relative efficacy of VenG and ClbG vs. other selected comparators was estimated. Health state utilities and adverse event (AE) disutilities were derived from a systematic literature review and published health-technology assessment reports. To generate total quality-adjusted life years (QALYs), these health state utilities and AE disutilities were applied to the relative efficacy data. The cost of medication was based on country level drug prices. The healthcare resources used were validated by local experts through a Delphi panel methodology. Costs of resources used for routine medical attention and the management of adverse events were based on tariffs from social security system of Argentina. Costs were expressed in Argentine Pesos (AR$) (exchange rate 1 US dollars ($) = 100.75AR$, July 2021). A 5% annual discount rate was applied for costs and outcomes. Cost-effectiveness results are presented in terms of incremental cost per QALY. A new treatment that is both lower in total cost and more efficacious (in QALYs) vs. identified comparator treatments is described as being “dominant”. Uncertainty in the model was tested through one-way sensitivity analyses (OWSA) and probabilistic sensitivity analyses (PSA) Results: Over a 30-year time horizon, the total discounted costs were, for VenG, $117,250.19; ClbG, $167,675.26; BR, $206,951.64; and IBR, $432,243.36. The benefits in the cost-effectiveness model (CEM) were measured in terms of total discounted QALYs which were 5.634 for VenG, 5.350 for ClbG, 4.996 for BR and 5.161 for IBR. The incremental discounted QALYs of VenG was: 0.284 vs. ClbG, 0.639 vs. BR, and 0.473 vs. IBR. Thus, VenG with a 12-month fixed duration, has lower total costs and is more efficacious (“dominant”) over all comparators in the CEM. OWSA analyses show that the results are robust, and in the PSA VenG is dominant over all the comparators considered, ICER is ≤$ 6,011.20 (1 GDP per capita for Argentina, 2020), /QALY in 97% of the iterations CE Results - VenG ClbG BR IBR Costs $ 117,250.19 $ 167,675.26 $ 206,951.64 $ 432,243.36 LYs 12.80 12.80 11.88 11.88 QALYs 5.634 5.350 4.996 5.161 Incremental cost (vs VenG) $ -50,425.06 $ -89,701.44 $ -314,993.17 Incremental QALYs 0.284 0.639 0.473 Cost/QALYs gained Dominant Dominant Dominant Summary/Conclusion: This study shows that in Argentina, VenG would be dominant treatment option (better results and lower costs) compared with ClbG, BR and IBR in the treatment of first-line unfit CLL patients.

PB1877: ADJUSTING SURVIVAL DATA FOR TREATMENT CROSSOVER IN THE ELEVATE-TN TRIAL BY USING A HISTORICAL COHORT OF PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY IN FRONT-LINE CHRONIC LYMPHOCYTIC LEUKEMIA

Background: Acalabrutinib (A) is a next-generation Bruton tyrosine kinase inhibitor (BTKi) approved for chronic lymphocytic leukemia (CLL) treatment. ELEVATE-TN trial interim data (~47 months median follow-up [FU]) did not show survival benefit for A±obinutuzumab (O) versus chlorambucil+obinutuzumab (C+O) despite significantly superior progression-free survival (PFS). One explanation is C+O-to-A patient crossover (39%), which may have provided added overall survival (OS) benefit to the C+O arm. Aims: We evaluated OS by adjusting for crossover using a historical C+O cohort. Methods: The CLL11 trial demonstrated superior PFS and OS for C+O versus C and C+rituximab in first-line CLL prior to BTKi availability. Therefore, OS data for BTKi-naive C+O patients were digitized and compared with A±O from ELEVATE-TN. Individual patient datasets were used to plot Kaplan-Meier (KM) curves and calculate hazard ratios (HR) using Cox regression in R software. To validate our hypothesis (impact of crossovers on relative survival benefit), we compared 28-month FU data from ELEVATE-TN, where we observed lower OS HRs (non-significant) to CLL-11 data until that time period. The CLL11 and ELEVATE-TN trials enrolled patients with similar baseline characteristics; however, this analysis did not account for within-trial heterogeneity. Results: There was a statistically significant reduction in risk of death with all 3 ELEVATE-TN treatments (47-month FU data) versus CLL-11 C+O: A+O versus C+OCLL11 (HR=0.23 [95% CI=0.12-0.42, p<0.001]); A versus C+OCLL11 (HR=0.43 [95% CI=0.27-0.70, p<0.001]); C+O versus C+OCLL11 (HR=0.44 [95% CI=0.27-0.71, p<0.001]). In the additional analysis with 28-month FU data, comparing ELEVATE-TN arms with C+O from CLL-11, KM curves for C+O overlapped (HR=0.79 [95% CI=0.42-1.47], p>0.05), indicating no difference. However, HRs for A+O versus C+OCLL11 (HR=0.39 [95% CI=0.18-0.84], p=0.02) and for A versus C+OCLL11 (HR=0.48 [95% CI=0.24-0.99], p<0.05) were statistically significant. Summary/Conclusion: The non-statistically significant OS for A±O versus C+O was likely due to treatment crossover. Conducting a treatment-switching analyses was challenging due to immature OS data; however, this analysis supports the hypothesis that crossover to A bolstered ELEVATE-TN C+O OS.

Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities

BackgroundGLOW is a phase 3 trial evaluating the efficacy and safety of ibrutinib-venetoclax in older patients and/or those with comorbidities with previously untreated chronic lymphocytic leukemia (CLL).MethodsWe randomly assigned (1:1) patients 65 years of age or older or those 18 to 64 years of age who also had a Cumulative Illness Rating Scale (CIRS) score greater than 6 (CIRS scores range from 0 to 56, with higher scores indicating more impaired function of organ systems) or creatinine clearance of less than 70 ml/min, to ibrutinib-venetoclax (3 cycles ibrutinib lead-in, then 12 cycles ibrutinib-venetoclax) or chlorambucil-obinutuzumab (6 cycles). The primary end point was progression-free survival (PFS) assessed by an independent review committee. Secondary end points included undetectable minimal residual disease (uMRD), response rates, and safety.ResultsThis study enrolled 211 patients, with 106 randomly assigned to ibrutinib-venetoclax and 105 to chlorambucil-obinutuzumab. With a median follow-up of 27.7 months, there were 22 PFS events for ibrutinib-venetoclax and 67 events for chlorambucil-obinutuzumab. PFS was significantly longer for ibrutinib-venetoclax than for chlorambucil-obinutuzumab (hazard ratio, 0.216; 95% confidence interval [CI], 0.131 to 0.357; P<0.001). The improvement in PFS with ibrutinib-venetoclax was consistent across predefined subgroups, including patients 65 years of age or older or with a CIRS score greater than 6. The best uMRD rate in bone marrow by next-generation sequencing was significantly higher for ibrutinib-venetoclax (55.7%) than for chlorambucil-obinutuzumab (21.0%; P<0.001). The proportion of patients with sustained uMRD in peripheral blood from 3 to 12 months after end of treatment was 84.5% for ibrutinib-venetoclax and 29.3% for chlorambucil-obinutuzumab. Four patients treated with ibrutinib-venetoclax required subsequent therapy compared with 27 patients receiving chlorambucil-obinutuzumab (hazard ratio, 0.143; 95% CI, 0.050 to 0.410). Adverse events grade 3 or greater occurred for 80 (75.5%) and 73 (69.5%) patients receiving ibrutinib-venetoclax and chlorambucil-obinutuzumab, respectively, with neutropenia being most common in both arms (37 [34.9%] and 52 [49.5%]). There were 11 (10.4%) and 12 (11.4%) all-cause deaths in the ibrutinib-venetoclax and chlorambucil-obinutuzumab arms, respectively.ConclusionsIbrutinib-venetoclax, an all-oral, once-daily, fixed-duration combination, demonstrated superior PFS and deeper and better sustained responses versus chlorambucil-obinutuzumab as first-line CLL treatment in older patients and/or those with comorbidities. (Funded by Janssen Research & Development, LLC, and Pharmacyclics; ClinicalTrials.gov number, NCT03462719.)

Combined Ibrutinib and Venetoclax for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): Focus on Long-Term MRD Results

Combined Ibrutinib and Venetoclax for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): Focus on Long-Term MRD Results

High Rates of Undetectable Minimal Residual Disease Remissions with Time-Limited Bendamustine, Rituximab, and Venetoclax (BR-VR) in Untreated Chronic Lymphocytic Leukemia (CLL)

High Rates of Undetectable Minimal Residual Disease Remissions with Time-Limited Bendamustine, Rituximab, and Venetoclax (BR-VR) in Untreated Chronic Lymphocytic Leukemia (CLL)

Single-Agent Ibrutinib Versus Real-World (RW) Treatments for Patients with Previously Untreated Chronic Lymphocytic Leukemia (CLL): Adjusted Comparison of Resonate-2™ with the Cllear and Lyon-Sud Rw Databases

IntroductionIbrutinib, a once-daily oral Bruton's tyrosine kinase inhibitor, has shown progression-free survival (PFS) or overall-survival (OS) benefit over chemoimmunotherapy (CIT) in multiple phase 3 studies in previously untreated patients with CLL, and significantly longer time to next treatment compared with CIT in previously untreated high-risk patients in a RW setting. We conducted an adjusted comparison of ibrutinib versus RW treatment for previously untreated CLL using patient-level data from the phase 3 RESONATE-2™ (NCT01722487) trial and RW databases from 2 countries.MethodsPreviously untreated patients with CLL, fulfilling RESONATE-2™ eligibility criteria (age ≥ 65, no del17p) were selected from 2 RW data sources containing electronic medical records for patients with CLL: Centre Hospitalier Lyon-Sud, France; CLLEAR CLL registry from 7 academic centers in the Czech Republic. PFS and OS were compared between patients from the ibrutinib arm of RESONATE-2™ with a median follow-up of 60 months, and those receiving physicians' choice (PC) treatment other than ibrutinib from the RW database, adjusting for differences in baseline characteristics including age, gender, del11q, IGHV status, RAI/BINET disease stage, and Eastern Cooperative Oncology Group (ECOG) score. Hazard ratios (HRs) for ibrutinib versus RW PC treatment were estimated using a multivariable Cox proportional hazards model including available baseline characteristics as covariates, and using an inverse probability weighted (IPW) Cox model with average treatment effect for treatment (ATT) weights derived from propensity scores estimated from a logistic regression including the same covariates.ResultsThe analysis included 136 patients from the RESONATE-2™ study receiving ibrutinib and 920 previously untreated RW patients receiving PC treatment (Lyon-Sud n = 162, CLLEAR n = 758). Baseline characteristics were generally balanced between treatment groups. The most common PC regimens contained CIT and were fludarabine + cyclophosphamide + rituximab (FCR) (n = 227), bendamustine + rituximab (BR) (n = 201), and rituximab + chlorambucil (R + Chlor) (n = 116). Older age, male gender, del11q and advanced disease stage were independent risk factors for PFS and OS. When comparing ibrutinib versus the overall PC cohort, the adjusted HR (95% confidence interval [CI]) was 0.24 (0.16-0.34) for PFS and 0.33 (0.21-0.52) for OS (both p < 0.0001). IPW-based comparative estimates were highly consistent for both PFS (HR = 0.27 [0.18-0.39]) and OS (HR = 0.39 [0.24-0.62]). ATT-weighted survival curves estimating PFS and OS for the RESONATE-2™ population as if treated with PC, showed a median value of 32.1 months and 72.5 months, respectively, while median values for Ibrutinib were not reached. When comparing ibrutinib versus FCR, BR, and R + Chlor, the adjusted HRs (95% CI) were 0.26 (0.17-0.38), 0.27 (0.18-0.41), and 0.27 (0.17-0.42), respectively, for PFS and 0.34 (0.20-0.56), 0.28 (0.16-0.49), and 0.61 (0.32-1.13), respectively, for OS (Figure).ConclusionsAdjusted comparisons of the RESONATE-2™ trial and RW patient-level data demonstrates significantly improved PFS and OS for ibrutinib versus physician's choice treatment (predominantly CIT) in previously untreated patients with CLL. PFS and OS benefit for ibrutinib was consistent across a range of common regimens: FCR, BR, and R + Chlor. These results are consistent with data from phase 3 studies and support the use of ibrutinib for first-line CLL treatment.Funding Source:Sponsored by Janssen Pharmaceutica NV, and Pharmacyclics LLC, an AbbVie Company. The RW databases are independently owned. Writing assistance was provided by Emma Fulkes and Liqing Xiao of Parexel and funded by Janssen Pharmaceutica NV. [Display omitted] DisclosuresDoubek: Janssen-Cilag, AbbVie, AstraZeneca, Amgen, Gilead, Novartis: Honoraria, Research Funding. Smolej: AbbVie, AstraZeneca, Gilead, Janssen-Cilag, and Roche: Consultancy, Honoraria, Other: Travel Grants. Šimkovič: AbbVie, AstraZeneca, Janssen-Cilag, Gilead, Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants. Lysak: Novartis, Janssen-Cilag, AbbVie; AstraZeneca: Honoraria, Research Funding. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Ferrant: AbbVie: Honoraria, Other: Travel, Accommodations, Expenses; AstraZeneca: Honoraria; Janssen: Other: Travel, Accommodations, Expenses. Diels: Janssen: Current Employment. Cabrieto: Janssen: Current Employment. Nielsen: Janssen: Current Employment. Salles: Allogene: Consultancy; Regeneron: Consultancy, Honoraria; Velosbio: Consultancy; Takeda: Consultancy; Rapt: Consultancy; Genentech/Roche: Consultancy; Epizyme: Consultancy, Honoraria; Debiopharm: Consultancy; Genmab: Consultancy; Incyte: Consultancy; Ipsen: Consultancy; Janssen: Consultancy; Kite/Gilead: Consultancy; Loxo: Consultancy; Miltneiy: Consultancy; Morphosys: Consultancy, Honoraria; Novartis: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria.

Efficacy and Safety of First-Line Therapy with Chlorambucil, Rituximab and Individualized Dose Lenalidomide in FCR-Unfit Patients with Advanced Chronic Lymphocytic Leukemia (CLL): A Phase I/II HOVON Trial

Efficacy and Safety of First-Line Therapy with Chlorambucil, Rituximab and Individualized Dose Lenalidomide in FCR-Unfit Patients with Advanced Chronic Lymphocytic Leukemia (CLL): A Phase I/II HOVON Trial

Insurance Design and Out-of-Pocket (OOP) Costs: a Comparison of Oral and Intravenous (IV) Treatment Plans for Chronic Lymphocytic Leukemia (CLL) in the Era of the Affordable Care Act (ACA)

BackgroundPatients on treatment for CLL can incur significant OOP costs, but little is known about length of time to reach OOP maximums, and variance of cost-sharing between IV and oral medications, especially among privately-insured patients. These issues have both practice and policy implications. First, from a practice perspective, insurance plans can vary their cost-sharing for IV versus oral chemotherapy, and cost-sharing can impact adherence and outcomes. Second, from a policy perspective, 43 states have enacted laws to ensure cost-sharing parity between oral and IV chemotherapy, but there is little evidence that these laws actually lower costs for patients. Thus, our objective was to determine, for both oral and IV drugs, how quickly patients reach their annual OOP maximums.MethodsUsing Health Insurance Marketplace Public Use Files that contain cost-sharing data for all private insurance plans participating in the Affordable Care Act's (ACA) Federally Facilitated Marketplace, we determined the relative impact on OOP cost of oral (ibrutinib) vs. IV (bendamustine/rituximab; BR) chemotherapy on time to reaching OOP maximums. With this data, we created a model of guideline-based, first-line CLL treatment regimens for ibrutinib and BR. We used Current Procedural Terminology (CPT) codes for procedures, and Healthcare Common Procedure Coding System (HCPCS) J-codes for drugs. We used a patient weight of 70kg and body surface area of 1.8m2 for dosing. Ibrutinib was dosed at 420mg. BR was dosed at bendamustine 70mg/m2 and rituximab 375mg/m2 for the first dose and bendamustine 500mg/m2 for all subsequent doses. We accounted for billing of professional fees, facility fees, infusional drugs, oral specialty drugs, supportive care medications, imaging, and blood tests. The average bill for each visit was applied to ACA Marketplace plans at 100% of Medicare fee schedule. As a sensitivity analysis, we varied costs to 120% and 150% of the Medicare Fee schedule based on an evidence-based multiplier for estimation of private insurance fees. Descriptive statistics and t-tests for comparison were calculated for number of days to reach OOP maximum for each insurance plan. We assessed variation according to metal tier (Catastrophic, Bronze, Silver, Gold, Platinum).ResultsOf the nearly 55,000 ACA plans nationally, 3092 unique insurance plan designs were identified on the ACA Marketplace for 2017. The average OOP maximum of these plans by metal tier was $7150 for catastrophic (maximum allowed by the ACA in 2017), $6883 for bronze, $6463 for silver, $4931 for gold, and $2284 for platinum. On average, patients on 95% of plans will reach the OOP maximum for the year for both BR and ibrutinib. A patient on BR will reach the OOP maximum in a mean of 3 clinic visits (29 days) for 100%, 120% and 150% of Medicare pricing. Using the 100% Medicare pricing estimate, a patient on ibrutinib will reach the OOP maximum in a mean of 3 visits (36 days) based on the typical timing of office visits. For the 120% and 150% of Medicare pricing estimates, the maximum OOP costs for ibrutinib are reached after only 2 visits (8 days). Metal tier also impacted time to maximum. For a patient on BR at 100% of Medicare, the maximum OOP expense was reached after 1 visit (1 day) for catastrophic, 2 visits (2 days) for bronze, 3 visits (28 days) for silver, 4 visits (29 days) for gold, 10 visits (113 days) for platinum. For a patient receiving ibrutinib at 100% of Medicare, the maximum OOP expense was reached after 1 visit (1 day) for catastrophic, 2 visits (8 days) for bronze, and 3 visits (28 days) for silver, gold, and platinum.ConclusionsFirst, using standard Medicare pricing, we found that patients receiving BR or ibrutinib quickly reached their maximum annual OOP caps within an average of 29 days (3 clinic visits) for BR and 36 days (3 visits) for ibrutinib. Using pricing schedules more reflective of private insurance, patients are likely to reach their cap even faster. Second, drug costs contributed most to reaching the maximums despite accounting for standard professional fees, labs, and imaging. These data suggest a limited benefit of state parity laws since the underlying costs of these drugs remain high, and patients reach OOP caps very quickly with either oral or IV drugs. Methods for reducing the financial burden to the patient and health care system from these novel yet expensive therapies need to be explored. DisclosuresZafar:Novartis: Other: Spouse's Employment.

PCN164 Impact of Treatment and Patient Attributes on Oncologists Decision-Making in First-line Chronic Lymphocytic Leukemia (CLL) in the United States (US)

This study evaluated the impact of treatment and patient attributes on oncologists’ first-line CLL treatment decisions. This cross-sectional survey assessed board certified medical oncologists practicing and treating CLL patients in the US (October 2019 - January 2020). Survey included a ranking exercise of 13 treatment attributes pertaining to efficacy, adverse effects, and convenience selected from literature, on their relative importance in treatment decision-making. Four clinical vignettes with varying patient attributes (age, gender, IGHV mutation status, etc.) were presented to oncologists to understand their treatment selection process. Other items included demographics, clinical practice type, cytogenetic/mutation testing recommendations, and patient participation in treatment decisions. Results were descriptively analyzed. Fifty oncologists (oncology: 28%, hematology: 10%, both: 62%) completed the survey; most were males (86%), Caucasian (43%), community-based (60%)and treating 53 CLL patients on average with a mean experience of 14 years. Oncologists ranked overall survival, progression free survival, grade III/IV tumor lysis syndrome, grade III/IV atrial fibrillation, and administration route (oral vs intravenous) as the top-five most important treatment attributes. Most clinicians (84%) “often/always” recommended cytogenetic/mutation testing. Vignette responses showed that most oncologists (mean 61%) preferred oral targeted monotherapy as their treatment choice for IGHV mutated/unmutated CLL patients; for older patients this preference was more prominent (mean 67% among vignettes with age 75+). Furthermore, oncologists consistently cited efficacy among the top-two reasons for treatment selection. Most oncologists stated they “completely/somewhat” (84%) understood their patients’ treatment preferences/goals, and their patients had “complete/some” participation (92%) in treatment decision-making. Oncologists considered efficacy as the most important attribute and preferred oral targeted monotherapy for first-line CLL patients. In contrast to previously published real-world testing patterns in CLL, a higher proportion of clinicians recommended cytogenetic/mutation testing. This study is an important step in understanding how treatment and patient attributes impact clinician recommendations

Oncologist and Patient Preferences for Novel Agents in First-Line Treatment for Chronic Lymphocytic Leukemia: Commonalities and Disconnects.

PurposeTreatment for chronic lymphocytic leukemia (CLL) has changed dramatically with the approval of novel agents. Information regarding how patients and oncologists make trade-offs across attributes of novel therapies is limited. The purpose of this study was to understand how variations in attributes impact treatment choice among patients and oncologists.Patients and MethodsIn this study, 371 participants (patients [n=220] and oncologists [n=151]) completed an online discrete choice experiment (DCE) to quantify preferences for first-line (1L) CLL treatment with novel agents; participants chose between hypothetical treatment profiles consisting of eight attributes with varying levels taken from published literature. Hierarchical Bayesian models were used to estimate attribute level preference weights. The weights were used to compute relative importance, a measure of how influential an attribute is to treatment choice.ResultsIncreasing 2-year progression-free survival (PFS) from 75% to 95% had the greatest impact on preferences in 1L CLL treatment, accounting for 40% and 30% of the variation in preferences among patients and oncologists, respectively. Risk differences in atrial fibrillation (AF), infection, and discontinuation due to adverse events (AEs) were also important to patients and oncologists. Among both groups, risk differences in tumor lysis syndrome (TLS) and bleeding were least influential in treatment choice. Oncologists required 2–4 times higher increases in 2-year PFS than patients to accept increased risks of AF, discontinuation due to AEs, bleeding, TLS, and arthralgia/myalgia.ConclusionPatient–oncologist communication may be improved by a more focused discussion on the risks of AEs, relative to treatment outcomes, with patient goals in mind.

Cost-Effectiveness of a 12-Month Fixed Duration of Venetoclax in Combination with Obinutuzumab Versus Chemoimmunotherapy and Other Novel Combinations in First-Line Chronic Lymphocytic Leukemia in Canada

OBJECTIVES: To estimate the cost-effectiveness of venetoclax + obinutuzumab (GAZYVA®, G), (VEN+G) in the treatment of first-line (1L) chronic lymphocytic leukemia (CLL) from a Canadian health care system cost perspective. METHODS: A three-state partitioned-survival model was used to extrapolate progression-free survival (PFS) and overall survival (OS) over a 10-year time horizon. Cost-effectiveness was estimated comparing 12-month fixed duration of VEN+G versus (vs) G + Chlorambucil (GClb) based on the CLL14 clinical trial (NCT02242942). Other comparators included Bendamustine + rituximab (BR), Chlorambucil + rituximab (Clb+R), Ibrutinib (Ibr), Acalabrutinib (Acala) and Acalabrutinib + GAZYVA (Acala+G). VEN+G was also compared to the combination of fludarabine, cyclophosphamide and rituximab (FCR) in the overall 1L CLL population which included unfit and fit patients. Relative efficacy of VEN+G vs other comparators was estimated using a network meta-analysis. Health state utilities and adverse event disutilities were derived from a systematic literature review and other published sources. Costs included CLL treatment, routine care and monitoring, adverse events, disease progression costs, subsequent treatment costs, and end of life care. Uncertainty was assessed using an underlying probabilistic model (probabilistic analysis of uncertainty generated from 5,000 iterations), through deterministic sensitivity analyses (i.e., one-way sensitivity analyses (OWSA)), and through a series of alternative scenario analyses. RESULTS: For the overall unfit 1L CLL patient population, the probabilistic total discounted costs incurred over a 10-year time horizon were as follows: $217,727 for VEN+G vs $312,287 for GClb, $399,219 for BR, $380,713 for Clb+R, $736,017 for Ibr, $868,797 for Acala and $916,139 for Acala+G. The probabilistic total discounted quality adjusted life years (QALYs) were 4.964 for VEN+G vs 4.750, 4.550, 4.422, 4.709, 5.269, and 5.359, respectively for the comparators. For the overall 1L CLL patient population, the probabilistic total discounted costs were $219,651 for VEN+G vs $312,570 for GClb, $342,195 for FCR, $397,262 for BR, $380,551 for Clb+R, $757,129 for Ibr, $868,388 for Acala, and $916,798 for Acala+G. The probabilistic total discounted QALYs were 5.888 for VEN+G vs 5.519, 5.067, 5.198, 5.073, 5.597, 6.259 and 6.380, respectively for the comparators. VEN+G was found to be less costly and more efficacious (i.e., dominant) compared to GClb, BR, Clb+R, Ibr and FCR. As a result, incremental cost utility ratios (ICERs) were not calculated for these comparators. Acala and Acala+G resulted in ICERs ranging from $1.4-$2.1 million per QALY gained relative to VEN+G, which is not cost-effective. Based on the probabilistic model and 5,000 simulations, VEN+G was found to be at least 97% cost-effective across all decision maker willingness-to-pay thresholds. The results from the deterministic model were found to be similar to the probabilistic model. Using the deterministic model, and in comparison to the most commonly prescribed treatment for 1L CLL in Canada (i.e., Ibr), the OWSA comparing VEN+G to Ibr found that the most influential variables in the model were the PFS and OS hazard ratios for Ibr and the utility values for PFS and post-progression survival. CONCLUSION: VEN+G is an effective novel fixed duration treatment option which leads to deep and durable responses for the treatment of patients with unfit 1L CLL and provides excellent value-for-money compared with existing chemoimmunotherapy and treat to progression novel combinations. Disclosures Chatterjee: Pharmerit: Current Employment. Van de Wetering:Pharmerit: Current Employment. Goeree:AbbVie Inc.: Consultancy. Desbois:AbbVie Inc.: Current Employment, Current equity holder in publicly-traded company. Manzi:AbbVie Inc.: Current Employment, Current equity holder in publicly-traded company. Manzoor:AbbVie: Current equity holder in publicly-traded company. Owen:AbbVie, F. Hoffmann-La Roche, Janssen, Astrazeneca, Merck, Servier, Novartis, Teva: Honoraria. Sail:AbbVie Inc.: Current Employment, Current equity holder in publicly-traded company.

Single-Agent Ibrutinib As First-Line Treatment for Patients with Chronic Lymphocytic Leukemia (CLL) in Routine Clinical Practice in Spain

Introduction. Ibrutinib is a first-in-class, oral, once-a-day Bruton's tyrosine kinase inhibitor that achieves high overall response rates and durable remissions in patients with chronic lymphocytic leukemia (CLL) including those with high-risk features (unmutated IGHV, TP53 abnormalities, 11q deletion). Survival with continuous single-agent ibrutinib in previously-untreated CLL patients is comparable to an age-matched general population (Figure 1). IBRORS is an observational, retrospective, multicentre study to describe the characteristics and clinical outcomes of patients with CLL treated with single-agent ibrutinib in routine clinical practice in Spain. This present analysis reviews the subset of patients in IBRORS who received ibrutinib as the first-line of treatment. This series includes a significant number of patients with high risk cytogenetic/molecular alterations (del17p/TP53 M), which corresponds with the approved indication for first-line CLL patients in Spain at the time. Methods. Adult patients diagnosed with CLL treated with single-agent ibrutinib in first-line, or at first or second relapse since its commercialization in Spain (between January 2016 to January 2019) were included in the IBRORS study. Clinical characteristics of patients, efficacy and tolerability of ibrutinib as first-line treatment were analyzed here. A Kaplan-Meier analysis was performed for overall survival (OS) and progression-free survival (PFS). Results. 84 patients, from a total of 269 included in IBRORS, received single-agent ibrutinib as first-line treatment. The median age was 71.3 years (range 63-77) at the time of ibrutinib initiation. 56.3% of patients presented with an intermediate/high-risk Rai-Binet stage, and the majority of patients (98.6%) had an ECOG PS of 0-1. 91.7% of patients had at least 1 high risk molecular cytogenetic factor (unmutated IGHV, TP53 abnormalities, 11q deletion or complex karyotype) described in table 1. Baseline comorbidities of patients are described in table 2. Concomitant medication included anticoagulants (9.5% patients; vitamin K antagonist [n=4], Apixaban [n=1] and LMWH [n=3] patients), antiplatelet agents (11.9% patients), and antihypertensives (50% patients). The overall response rate (ORR) was 79.5%; 14/84 (16.6%) achieved a complete response (CR), 14/84 (16.6%) achieved CR unconfirmed, 27/84 (32.14%) achieved a partial response (PR) and 12/84 (14.2%) a PR + lymphocytosis. The median PFS and OS were not reached, and the estimated PFS at 24 months was 84.5% (73.4-95.6%). OS and PFS curves are represented in figure 2. The PFS of each patient subgroup with high-risk cytogenetic characteristics was similar to that of all patients in the first-line cohort: del17p/TP53 mutation (HR = 0.963 [95% CI 0.188-4.928]; p = 0.964), del11q (HR = 0.042 [95% CI 0.000-682.736]; p=0.521), unmutated IGHV (HR = 0.391 [95% CI 0.110-1.394]; p = 0.148). The median duration of exposure to ibrutinib was 17.3 (11.9-25.6) months. Dose reduction of ibrutinib occurred in 17/84 (20.2%) patients, 8/84 (9.52%) due to toxicity (4 hematologic toxicity and 4 non-hematologic toxicity). 27/84 (32.1%) patients had temporary interruption of treatment. 15/84 (17.8%) patients permanently discontinued ibrutinib including 6 (7.14%) patients due to progression, 4 (4.76%) due to toxicity and 5 for other reasons. Safety: 49/84 (58.3%) patients developed at least one adverse event (AE), while 12/84 (14.2%) patients developed at least one serious adverse event (SAE). Twelve (14.3%) patients reported at least one haematological toxicity while 53 patients (63.1%) recorded at least one non-haematological toxicity. Only 1 patient experienced grade 3 atrial fibrillation, which did not lead to discontinuation. The most common AEs are described in table 3. Conclusion. This population of previously-untreated CLL patients, enriched for high-risk genomic features, reflects the initial approval of ibrutinib for the treatment of first-line patients with del17p in Spain. Single-agent Ibrutinib as the first-line treatment in this real world population was effective regardless of risk factors and well tolerated, with a low rate of discontinuation due to toxicity. Findings are consistent with those reported in clinical trials. Disclosures Loscertales: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria. Arguiñano:AbbVie: Honoraria; Janssen: Honoraria; BMS-Celgene: Honoraria; Novartis: Honoraria. 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. Pérez Persona:Amgen: Consultancy; Celgene: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Jannsen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy. Loriente:Janssen Cilag: Current Employment. Villanueva:Janssen Cilag: Current Employment.