Fixed-duration Therapy Research Articles

Real-world comparison of health care costs of venetoclax-obinutuzumab vs Bruton's tyrosine kinase inhibitor use among US Medicare beneficiaries with chronic lymphocytic leukemia in the frontline setting.

Bruton's tyrosine kinase inhibitors (BTKis) and the BCL-2 inhibitor venetoclax in combination with obinutuzumab (VEN-O) are both recommended as frontline therapy in chronic lymphocytic leukemia (CLL). However, VEN-O is a 12-month fixed-duration therapy generating durable remissions whereas BTKis are continuous treat-to-progression treatments. To examine costs before and after the fixed-duration treatment period for VEN-O relative to that observed for BTKis in a national sample of older US adults with CLL in the frontline setting. This retrospective analysis used Medicare Parts A, B, and D claims from 2016 to 2021. Fee-for-service Medicare beneficiaries aged 66 years or older initiating frontline CLL treatment with VEN-O or a BTKi treatment between June 1, 2019, and June 30, 2020 (index date = first prescription fill date), were included in the sample. Mean cost measures were captured for both groups over 2 fixed time periods calculated from the index date: Month 0 to 12 (proxy for VEN-O on-treatment period) and Month 13 to 18 (proxy for VEN-O off-treatment period). A difference-in-difference approach was used. Multivariate generalized linear models estimated changes in adjusted mean monthly costs during Month 0 to 12 vs Month 13 to 18, for the VEN-O group relative to the BTKi group. The final sample contained 193 beneficiaries treated with VEN-O and 1,577 beneficiaries treated with BTKis. Risk-adjusted all-cause monthly total costs were similar for VEN-O patients ($13,887) and BTKi patients ($14,492) between Month 0 and 12. Moreover, during Month 13 to 18, the mean monthly all-cause total costs declined by 67% for VEN-O ($13,887 to $4,462) but only by 10% for BTKi ($14,492 to $13,051). Hence, the relative reduction in costs across the 2 periods was significantly larger for VEN-O (-$9,425) vs BTKi (-$1,441) patients (ie, difference in difference = -$7,984; P < 0.001). Similar patterns were observed for CLL-related costs, with the substantially larger reductions in CLL-related total monthly costs (-$9,880 VEN-O vs -$1,753 BTKi; P < 0.001) for the VEN-O group primarily driven by the larger reduction in CLL-related monthly prescription costs (-$9,437 VEN-O vs -$2,020 BTKi; P < 0.001). This real-world study of older adults with CLL found a large reduction in monthly Medicare costs in the 6 months after completion of the fixed-duration treatment period of VEN-O, largely driven by the reduction in CLL-related prescription drug costs. A similar decline in costs was not observed among those treated with BTKis. Our study highlights the substantial economic benefits of fixed-duration VEN-O relative to treat-to-progression therapies like BTKis in the first-line CLL setting.

Glofitamab monotherapy in patients with heavily pretreated relapsed/refractory (R/R) mantle cell lymphoma (MCL): Updated analysis from a phase I/II study.

7008 Background: Glofitamab, a bispecific antibody with a novel 2:1 (CD20:CD3) format, engages and redirects T cells to eliminate malignant B cells. In a Phase I/II study (NCT03075696), fixed-duration glofitamab monotherapy showed high, durable complete responses (CR) and manageable safety in patients (pts) with heavily pretreated R/R MCL (Phillips et al. ASH 2022). We report updated efficacy and safety data for pts with R/R MCL. Methods: Pts received obinutuzumab pretreatment (Gpt; 1000mg or 2000mg) 7 days before their first glofitamab dose. Glofitamab step-up dosing was given on Cycle (C) 1 Day (D) 8 (2.5mg) and D15 (10mg), and target dose (16mg or 30mg) from C2D1 to C12 as a fixed-duration therapy. Efficacy endpoints were CR, overall response rate (ORR), duration of CR (DOCR), duration of response (DOR) and progression-free survival (PFS). Post-hoc PFS and overall survival (OS) landmark analyses were performed in pts with a CR at end of treatment (EOT). Results: As of Sept 4, 2023, 61 pts were enrolled; 60 received study treatment (1000mg Gpt, n=16; 2000mg Gpt, n=44). Median number of prior lines of therapy was 2 (range: 1–5); 73.3% were refractory to the last line of prior therapy. Median duration of glofitamab therapy was 7.4 months; median number of cycles was 12. Of the 31 pts (51.7%) who received prior Bruton’s tyrosine kinase inhibitor (BTKi) therapy, 29 (93.5%) were BTKi refractory; median number of prior lines of therapy was 3 (range: 1–5); 90.0% were refractory to the last line of prior therapy. At a median PFS follow-up of 17.2 months, ORR and CR rate were 85.0% and 78.3%, respectively. Median DOCR was 15.4 months; the majority of CRs (28/47; 59.6%) were ongoing at data cut-off. Of 19 pts with a CR, 9 had disease progression and 10 died (fatal adverse event [AE], n=8; COVID, n=7; septic shock, n=1). Estimated 12-month DOCR and DOR rates were 71.0% and 66.6%, respectively. Median PFS was 16.8 months. Landmark analyses indicated that most pts with a CR at EOT were alive and progression free 15 months post-EOT (OS rate, 72.7%; PFS rate, 59.2%). Observed efficacy data were consistent across both Gpt cohorts. In post-BTKi pts after a median PFS follow-up of 26.1 months, ORR and CR rate were 74.2% and 71.0%, respectively. Median DOCR was 12.6 months; median PFS was 8.6 months. No new safety signals were observed. Cytokine release syndrome (CRS) remained the most common AE (42/60, 70.0%; Grade 1/2, 58.3%) and was lower in the 2000mg (63.6%) vs the 1000mg (87.5%) Gpt cohort. Glofitamab monotherapy (2000mg Gpt) is currently under investigation in the Phase III GLOBRYTE study (NCT06084936). Conclusions: Fixed-duration glofitamab continues to demonstrate compelling response rates that are maintained beyond EOT, with long-term durability observed in heavily pretreated pts with R/R MCL, including pts with prior BTKi therapy. The safety profile was manageable and CRS mainly low grade. Clinical trial information: NCT03075696 .

Innovative Combinations, Cellular Therapies and Bispecific Antibodies for Chronic Lymphocytic Leukemia: A Narrative Review.

In the last few years, several agents targeting molecules that sustain the survival and the proliferation of chronic lymphocytic leukemia (CLL) cells have become clinically available. Most of these drugs target surface proteins, such as CD19 or CD20, via monoclonal or bispecific monoclonal antibodies (BsAbs), CAR T cells, intracellular proteins like BTK by using covalent or non-covalent inhibitors or BCL2 with first or second generation BH3-mimetics. Since the management of CLL is evolving quickly, in this review we highlighted the most important innovative treatments including novel double and triple combination therapies, CAR T cells and BsAbs for CLL. Recently, a large number of studies on novel combinations and newer strategic options for CLL therapy have been published or presented at international conferences, which were summarized and linked together. Although the management of treatment with a single continuous agent is easier, the emergence of protein mutations, long-term toxicities and costs are important concerns that favor the use of a fixed duration therapy. In the future, a measurable residual disease (MRD)-guided treatment cessation and MRD-based re-initiation of targeted therapy seems to be a more feasible approach, allowing identification of the patients who might benefit from continuous therapy or who might need a consolidation with BsAbs or CAR T cells to clear the neoplastic clone.

Prognostication in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western countries. CLL is a highly heterogeneous disease: some patients may never require therapy and others relapse several times after different therapeutic strategies. Therefore, in CLL, prognostic markers are essential to capture high-risk patients for different clinical endpoints including early treatment requirement, early progression after BTK or BCL2 inhibitors and Richter transformation. In early stage CLL, different biological and clinical biomarkers have been identified to predict time to treatment requirement that could be used to identify the most appropriate population for early intervention clinical trial. However, at the moment, the standard of care for early stage CLL remains watch & wait since no survival benefit has been identified in clinical trials with chemoimmunotherapy and with BTK inhibitors. In patients requiring treatment TP53 disruptions identify high-risk patients who benefit the most from long-term continuous therapy with BTKi. On the opposite side of the spectrum, IGHV mutated patients devoid of TP53 disruption benefit the most from fixed-duration therapy with venetoclax-obinutuzumab. In between, the highly heterogenous subgroup of patients with IGHV unmutated genes represents the group in which further efforts are needed to identify additional prognostic biomarkers aimed at selecting patients who can benefit from fixed-duration and patients who can benefit from long term BTKi therapy. In the context of the aggressive transformation of CLL, namely Richter syndrome, the clonal relationship to the CLL counterpart represents the strongest prognostic biomarker. Clonally related Richter syndrome still represents an unmet clinical need which requires further efforts to identify new therapeutic strategies.

Predictors of Outcomes with Venetoclax-Based Treatment in Patients with Progressive Disease or Intolerance after Covalent BTK Inhibitors

Background: Venetoclax (Ven) is a standard of care for the treatment of patients (pts) with CLL/SLL. In the relapsed setting, there is very limited data on the efficacy of Ven after covalent BTK inhibitors ([cBTKi], ibrutinib, acalabrutinib, or zanubrutinib), and there is no prospective trial data on the feasibility of a Ven-based fixed-duration therapy after cBTKi failure. Recently, novel treatment options like pirtobrutinib, a non-covalent BTKi, have shown high efficacy after cBTKi, prompting scrutiny of Ven-based therapies after cBTKi failure, including Ven monotherapy and combination treatment with anti-CD20 antibodies. In this study, we aim to evaluate: 1) The efficacy of Ven-based therapy after cBTKi, 2) Predictors of the efficacy of Ven in this setting, and 3) The feasibility of fixed-duration therapy with Ven after BTKi. Methods: In this single-institution, retrospective study, we used our institutional CLL registry to identify patients with a CLL/SLL diagnosis who received Ven (with or without anti-CD20 antibodies) for at least two months after prior treatment with a cBTKi. Patient-level clinical data were extracted from electronic medical records. Progressive disease (PD) was defined by the treating physician based on clinical, laboratory, and/or imaging data. Progression-free survival (PFS) and Overall survival (OS) were calculated using the Kaplan-Maier estimates. Results: We identified 80 pts who started Ven between 1/2016-12/2022 after prior treatment with a cBTKi. Median age was 62 (range: 40-80), and 53% were male. FISH abnormalities included: 58% del17p, 25% del11q, 48% del 13q, and 19% with trisomy 12. The median prior lines of treatment were 2 (range: 1-7). Prior first cBTKis were ibrutinib (92.5%), acalabrutinib (6.5%), and zanubrutinib (1.5%). A total of 7 pts (9%) received more than one prior cBTKi (1 ibrutinib, 6 acalabrutinib). Prior cBTKi was used as first-line treatment in 21 pts (26%), and 51 (64%) pts received prior treatment with chemotherapy. The median duration of cBTKi treatment was 25 months (range 1-92). Reasons for cBTKi discontinuation were PD (n=56, 70%) and intolerance (n=24, 30%). Most pts started Ven-based therapy immediately after cBTKi (n=53, 66%), although 21 (26%) received one interim line, and 6 (7.5%) received more than one interim line. Ven was used either as monotherapy (n=45, 56%) or with anti-CD20 antibodies (n=35, 44%). The median time on Ven was 11 months (2-55 months). At the time of analysis, 75% of pts had stopped Ven, with the most common reason for discontinuation being PD (31, 53%), followed by treatment completion (19, 32%). Median PFS after starting Ven was 29 months (95% CI: 17-44) for the entire cohort. Median PFS was significantly inferior in pts who experienced PD on prior cBTKi compared with those who were intolerant to prior cBTKi (17 months vs. 55 months, p=0.002). Inferior PFS was also observed in patients with del17p (7 months vs. 26 months without del17p, p=0.003) and in pts who received Ven monotherapy vs. combination therapy with anti-CD20 antibodies (21 months vs. not reached, p=0.01). There was no difference in PFS based on prior treatment with chemotherapy or for pts who received treatments between cBTKi and Ven. In multivariable analysis, having del17p (HR 3.04, 95%CI [1.38-6.65]), Ven monotherapy (HR 3.19, 95% CI [1.52-6.68]) and PD on prior cBTKi (HR 4.29, 95% [1.50-12.29]) were associated with inferior PFS. With a median of 28 months of follow-up, 26 pts (32%) stopped Ven and did not experience PD. This included 23% of pts with PD after prior cBTKi and 54% of pts intolerant to prior cBTKi (p=0.007). Conclusion: Venetoclax-based therapy after cBTKi provides disease control, but not to the extent reported by the only prospective trial in this setting (Jones, Lancet Oncol, 2018). Inferior PFS was observed in pts who had PD after prior cBTKi (vs. being intolerant), pts who received Ven monotherapy (vs. combined with anti-CD20 antibodies), and those with del17p. While this study may be limited in assessing the feasibility of fixed-duration Ven therapy after cBTKi, our results indicate that such an approach may only be feasible in a subset of pts who stopped cBTKi because of intolerance and not PD.

Total Therapy (TT)-4: A Phase 3 Trial Comparing L-TT4 and S-TT4 and Tandem Auto Transplants in Standard Risk Multiple Myeloma

BACKGROUND: In the context of the TT4 study, a phase 3 trial was conducted to investigate whether a modified fixed duration treatment approach, known as L-TT4, could reduce toxicity while maintaining efficacy in tandem transplants for low-risk multiple myeloma (MM) defined by gene expression profiling. Here we report final analysis of TT4 study with long-term follow up of 11.7 years. METHODS: Treatment modification involved reducing the number of induction and consolidation cycles from 2 cycles each in the standard S-TT4 regimen to 1 cycle in L-TT4. The transplant regimen in L-TT4 was further adjusted by administering melphalan in a fractionated schedule of 50mg/m2 per day for 4 days (MEL50x4), instead of a single high-dose (MEL200) to reduce toxicity. To compensate for the potential decrease in effectiveness, bortezomib, thalidomide and dexamethasone (VTD) added for synergy between MEL50x4 and VTD. Maintenance was with 3 years of bortezomib, lenalidomide and dexamethasone The goal of this trial was to evaluate the impact of these modifications on toxicity levels and treatment outcomes in patients undergoing tandem transplants for multiple myeloma. Patients were enrolled in the period of August 2008 until March 2016. Data cut-off was July,2023. Results: Our study consisted of 380 patients after excluding 2 patients who were identified as high-risk gene expression profile (S-TT4:238, L-TT4:142). Median age was 58.7 years (range: 30-76 years) with 11.6% of enrolled patients identified as African Americans. 91.4% of enrolled patients completed at least one auto transplant and 78.3% of patient completed tandem transplants. The median follow-up duration for all patients of 11.66 years (interquartile range: 10.11-13.27 years). Median progression free survival (PFS) was 6.54 years (95% confidence interval (CI): 5.75-7.72 years)) with 10-year PFS of 39% (95% CI: 34.3-44.4%). Median overall survival (OS) was 12.6 years (95% CI: 11.6 years-not reached (NR)) with 10-year OS of 58.4% (95% CI:53.5%-63.7%). No statistically significant difference between S-TT4 vs. L-TT4 (median PFS: 7.33 years (95% CI: 6.01-9.44 years), median OS: 13.1 years (95% CI:12.30 years-NR) vs. (median PFS: 5.74 years (95% CI: 4.63-7.41 years),median OS:11.8 years (95% CI:9.21 years-NR) with OS hazard ratio of L-TT4 vs. S-TT4 of 1.17 (95% CI: 0.86-1.58, p=0322). [Figure] PFS HR of L-TT4 vs. S-TT4 of 1.21 (95% CI: 0.94-1.56, P=0.132). Early mortality (defined as death in the first year of enrollment) occurred in 6.1% of enrolled patients. No difference in treatment related mortality was found between L-TT4 and S-TT4. Grade III-V toxicities and maximum grade for system organ classes with at least 5% of the population experiencing an event showed no difference between L-TT4 vs. S-TT4 in all adverse events except grade III/IV infections which was higher in L-TT4 (60% vs. 44%, p=0.002). Secondary acute myeloid leukemia (AML) and/or myelodysplastic syndrome (MDS) occurred in 21 (5.5%) patients with the median time from diagnosis to diagnosis of AML and/or MDS of 4.5 years. AML and/or MDS was more frequently seen in patients assigned to L-TT4 when compared to S-TT4 though this difference was not statistically significant (7% vs. 4.6, P=0.317 ) Conclusion: Fixed duration therapy including multi-agent chemotherapy and tandem autologous stem cell transplantation and 3 years of extended therapy resulted in excellent patients' outcomes with median OS of 12.6 years and at least one in three patients being progression free for at least 10 years. Conditioning with single high-dose (MEL200) as used in S-TT4 resulted in similar outcomes compared to fractionated MEL50x4 combined with VTD with better safety profile and thus should be the preferred approach.

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 &amp;gt;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 &amp;gt;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.

Patient and Physician Preferences for Fixed-Duration Vs Treatment to Progression Chronic Lymphocytic Leukemia (CLL) Treatments: Results from a Multi-Country Discrete Choice Experiment

Background Novel agents in chronic lymphocytic leukemia (CLL) have demonstrated improved outcomes while resulting in more complex treatment decision making. Agents vary in efficacy, tolerability, and duration of therapy, including fixed-duration (FD) therapy and treatment to progression (TTP) regimens, resulting in the need to make trade-offs in the selection of treatment. In the absence of mature overall survival data that clearly demonstrates long-term advantages of each regimen, it is important to understand the treatment preferences of patients and oncologists in the first line CLL setting. Aims We aimed to examine and quantify the preferences for key treatment attributes, including duration of therapy, of first line CLL therapies among oncologists and CLL patients. Methods Oncologists and CLL patients in the US, UK, Germany, France, and Australia were recruited into the study. They were asked to complete an online survey including a discrete choice experiment (DCE) where, in 12 tasks, participants were asked to choose between two hypothetical first-line therapies with levels that varied across five attributes: progression-free survival (PFS); risk of an adverse event (such as headache, muscle pain, or diarrhea); risk of treatment discontinuation due to side effect; FD intravenous (IV) regimens; FD and TTP oral regimens. The percentages of time each level was chosen when it appeared in a profile was reported. Bayesian models were used to estimate attribute level preference weights and attribute relative importance (RI) estimates, which capture how influential changes in an attribute are in treatment choice. Results In total, 259 oncologists (74% male, mean age: 50 + 8 years, mean years of practice: 17 + 6) and 192 patients (mean age 63 + 11 years; time since diagnosis 8 + 7 years; 69% treatment experienced) participated. Patients selected ‘daily oral medication taken indefinitely’ 40% of the time, which was significantly lower than the percentage of times they selected ‘daily oral medication taken for 24 months’ (53% of the time) and ‘daily oral medication taken for 12 months’ (54% of the time) (p&amp;lt;0.001). Conversely, there was no significant difference in the proportions of time that FD and continuous oral medications were selected by oncologists. Efficacy was the most important attribute for both patients and physicians, although more important for physicians than for patients (p&amp;lt;0.001), followed by reducing the risks of the two side effect attributes, which were similar in importance. Mode of administration attributes were not as important as efficacy and safety: changes in the oral regimens (FD therapy and TTP) was the fourth most important attribute, with patients placing a greater importance on this attribute compared to physicians (p&amp;lt;0.001); changes among the FD therapy IV regimens was least important. Changes in the oral and IV regimens were more important for patients than for physicians (p&amp;lt;0.001, Table). Patients with experience with FD therapies (n=101) had a higher preference for the 12-month FD oral regimens compared to those without FD therapy experience. Those with TTP regimen experience (n=73) had a higher preference for the TTP oral regimens compared to those without prior TTP therapy experience. There was no significant difference in attribute importance according to patient's treatment history (currently treated, previously treated but off treatment now, never treated). Conclusions In contrast to oncologists, patients preferred FD oral therapy over TTP regimens. Efficacy and safety of the medications were important to both patients and oncologists, and both were willing to make trade-offs in relation to duration of therapy if efficacy and safety were established. Our results suggest that patients may be more sensitive to type of regimen, whether it is FD or TTP than oncologists. Understanding factors that affect the preferences and perceptions of patients is important and may lead to improved treatment outcomes and better management of adverse events, leading to greater patient satisfaction. Further work is required to explore the determinants/drivers of these preferences.

Real-World Comparison of Healthcare Costs of Venetoclax-Obinutuzumab Vs. Btki Use Among Elderly U.S. Medicare Beneficiaries with Chronic Lymphocytic Leukemia in the Front-Line (1L) Setting

Background: Since the March 2016 FDA approval of ibrutinib as a front-line therapy in chronic lymphocytic leukemia (CLL), BTK inhibitors (BTKi) used as continuous therapy until progression or toxicity, are increasingly utilized early in the CLL treatment pathway. Conversely, the BCL-2 inhibitor venetoclax, approved for front-line (1L) CLL in May 2019, has been shown to generate durable responses. As a result, venetoclax has gained approval with a fixed treatment duration wherein a venetoclax plus obinutuzumab (VenO) regimen is to be completed after 12 months in the 1L setting. Fixed-duration therapy with a treatment-free remission has the potential advantage of lowering health care costs by avoiding continuous exposure to treatment. However, little real-world evidence has been generated to assess the potential economic benefits of a fixed-duration treatment such as VenO relative to treat-to-progression therapies like BTKis. The objective of this study was to examine healthcare costs before and after completion of the fixed-duration treatment period for VenO relative to that observed for BTKis in a national sample of elderly U.S. Medicare beneficiaries with CLL in the 1L setting. Methods: Our analysis used 2016-2021 100% Medicare Parts A, B, and D claims. Elderly fee-for-service Medicare beneficiaries initiating VenO (VenO group) or an available BTKi treatment (BTKi group) between 6/1/2019 and 6/30/2020 (index date = first prescription fill date) were included in the sample. Additional inclusion criteria for both groups were as follows: (a) ≥66 years old, (b) ≥1 diagnoses of CLL and no diagnoses for other indications of the index agent in the 12-month pre- and post-index period, (c) continuous medical and prescription coverage in the 36 months pre- and 12 months post-index period, (d) no prior CLL treatment in the 36-month pre-index period (i.e., to proxy 1L patients), and (e) continuous medical and prescription coverage from 13 to 18 months after the index date or until death if it occurs earlier (to capture costs after fixed-duration VenO treatment is completed). Healthcare cost measures included all-cause and CLL-related monthly total, prescription, and medical costs. Mean monthly cost measures were captured for both groups over two fixed time periods calculated from the index date: Month 0 to 12 (i.e. proxy for on-treatment period for VenO) and Month 13 to Month 18 (i.e. proxy for off-treatment period for VenO). Risk-adjusted monthly costs were estimated using generalized linear models controlling for differences in sociodemographic and clinical factors between the two groups. Difference-in-Difference method was used to assess reduction in costs across the two fixed time periods. Results: The final sample contained 193 patients (pts) in the VenO group (mean [SD] age 75.6 [5.5] years, 69.4% male, 90.2% White) and 1,577 pts in the BTKi group (mean [SD] age 77.6 [6.3] years, 55.8% male, 92.5% White). Between months 0 to 12, risk-adjusted all-cause monthly total costs were slightly lower for VenO pts ($13,887) than BTKi pts ($14,492) (Table 1). However, during months 13 to 18 the monthly all-cause total costs declined by 67% for VenO pts ($13,887 to $4,462) but only by 10% for BTKi pts ($14,492 to $13,051). Hence, the relative reduction in costs across the two periods was significantly larger for VenO (-$9,425) vs. BTKI (-$1,441) pts (i.e. Difference-in-Difference=-$7,984, p&amp;lt;0.001). Similar patterns were observed for CLL-related costs with the substantially larger reductions in CLL-related total monthly costs (-$9,880 VenO vs. -$1,753 BTKi, p&amp;lt;0.001) for the VenO group relative to BTKi group being primarily driven by the larger reduction in CLL-related monthly prescription costs (-$9,437 VenO vs. -$2,020 BTKi, p&amp;lt;0.001) (Table 1). Conclusions: This real-world study of elderly Medicare beneficiaries with CLL found a large reduction in monthly health care costs in the VenO group after the fixed-duration treatment period of 12 months. This drop was largely driven by the reduction in CLL-related prescription drug costs; however, similar declines were not observed in the BTKi group. Hence, the costs for pts on VenO after the fixed-duration treatment period were approximately $8000 per month lower than the BTKi group. Our study highlights the substantial economic benefits of VenO relative to treat-to-progression therapies like BTKis and carries implications for treatment decision-making CLL.

Patient Preferences for Fixed Versus Treat-to-Progression Therapies in Chronic Lymphocytic Leukemia

The treatment landscape for chronic lymphocytic leukemia (CLL) has evolved in the last 8 years to include novel targeted therapies as alternatives to chemoimmunotherapy. These treatments vary in their benefit-risk profiles, mode and frequency of administration, and duration of treatment. Previous preference studies in CLL have evaluated preferences for treatment attributes such as efficacy, tolerability, and mode and frequency of administration. However, few have assessed preferences for treatment duration independently of mode of administration. This study sought to further understand the factors that influence patient preferences for treatment duration and to quantify the tradeoffs that patients were willing to accept to have a fixed duration therapy versus a treat-to-progression therapy. The study was conducted in 2 phases: (1) a qualitative phase of in-depth individual interviews with patients to identify the factors that influence patient preferences for treating until progression versus a fixed duration as well as the CLL treatment attributes that patients consider most important, and (2) a quantitative phase to estimate the tradeoffs that patients would accept among CLL treatment attributes. In the qualitative phase, the semistructured interview guide included open-ended questions and probes to understand perceptions of fixed-duration treatments compared with treat-to-progression regimens and to elicit a list of treatment attributes that influence CLL treatment preference. The results of the interviews informed the development of a web-based discrete-choice experiment (DCE) survey. Respondents to the online survey answered 12 DCE questions, each offering a choice between 2 hypothetical treatment profiles defined by 7 attributes with varying levels, including treatment duration, which included levels for treat to progression and fixed duration for either 6 or 12 months. Data were analyzed using a random-parameters logit model, and estimated preference weights were used to calculate the maximum acceptable risk (MAR) of treatment-related adverse events the average respondent would accept in exchange for a move from a treat-to-progression to a fixed-duration therapy. The MAR is estimated as the ratio of the relative importance of an improvement in an attribute to the relative importance of a unit change in the level of risk (i.e., tumor lysis syndrome (TLS), atrial fibrillation, or fatigue). Interviews were conducted with 20 adults with a self-reported diagnosis of CLL. The mean age was 59 years, and 55% of participants (n = 11) identified as female. The mean time since diagnosis of CLL was 3 years, and 70% of participants (n = 14) had received treatment for CLL. Overall, 93 treatment attributes were spontaneously reported, including treatment duration. When probed, treatment duration was reported by 50% of participants as “very important” in their treatment decision. Almost all participants (n = 17) preferred a treatment with a fixed duration compared with treat-to-progression, assuming each had the same efficacy. Table 1 reports patients' perceived benefits and drawbacks of fixed-duration versus treat-to-progression therapies. The DCE survey was completed by 229 adults with a self-reported diagnosis of CLL for at least 3 months. The mean age was 66 years, and nearly 60% of the sample identified as female (n = 136). About 60% of the sample (n = 138) was diagnosed 5 or more years ago, and 152 respondents (66%) had experience with treatment for CLL. The results of the preference analysis showed that respondents preferred a fixed duration of either 6 months or 12 months versus treat-to-progression and, based on the MAR estimates, were willing to accept the following levels of risks to have a fixed-duration treatment versus treat to progression: more than a 3% increased risk of TLS, 6%-7% increased risk of atrial fibrillation, and 21%-26% increased risk of fatigue (Table 2). Past research has shown efficacy as the most important factor, yet qualitative interview participants also identified treatment duration as an important factor in their decision when choosing a CLL therapy. This finding was confirmed by the quantitative preference study, which revealed a preference for fixed-duration therapies over treat-to-progression regardless of the timeframe (6 or 12 months). Results from this study can help inform shared decision-making when considering alternative therapies for CLL.

EXABS-207-CLL Is Fixed-Duration Therapy the New Standard of Care in Frontline CLL?

EXABS-207-CLL Is Fixed-Duration Therapy the New Standard of Care in Frontline CLL?

Sequencing and combination of current small-molecule inhibitors for chronic lymphocytic leukemia: Where is the evidence?

Small-molecule inhibitors have revolutionized the treatment of chronic lymphocytic leukemia (CLL), a landscape once dominated by chemoimmunotherapy (i.e., an anti-CD20 monoclonal antibody in combination with systemic chemotherapy) in fit and unfit individuals. Key challenges include the management of refractory disease as well as the optimization of the therapy sequence. Decreased responsiveness has been observed with prolonged treatment, especially with Bruton tyrosine kinase (BTK) and phosphatidylinositol 3-kinase (PI3K) inhibitors which are given continuously, while venetoclax, an agent that targets dysregulations in intrinsic apoptosis signaling, has a fixed duration when combined with anti-CD20 monoclonal antibodies or BTK inhibitors. Combination therapy aims to synergistically target different oncogenic signaling pathways to abrogate the proliferation of resistant clones and thereby allows for fixed-duration treatments. An advantage of fixed-duration therapy is the potential to decrease financial and drug-induced toxicities. Sequencing of therapies is important to individualize treatment decisions based on factors such as age, comorbidities, tolerability, and patient preferences. However, to date, there are limited data to guide the rational sequencing or combination of these therapies, since conventional chemoimmunotherapy or chemotherapy regimens were used as comparators against these small-molecule inhibitors in trials that led to their regulatory approvals. In this article, we examined and evaluated the current evidence for sequencing versus the combination of small-molecule inhibitors for CLL by conducting comprehensive searches of the United States National Library of Medicine PubMed database, key meeting abstracts, and clinical practice guidelines. We also summarized findings from expert opinions to elucidate best practices for clinical scenarios with limited evidence to guide treatment selection.

Obinutuzumab plus chlorambucil versus ibrutinib in previously untreated chronic lymphocytic leukemia patients without TP53 disruptions: A real-life CLL campus study.

One of the main issues in the treatment of patients with chronic lymphocytic leukemia (CLL) deals with the choice between continuous or fixed-duration therapy. Continuous ibrutinib (IB), the first-in-class BTK inhibitor, and obinutuzumab-chlorambucil (G-CHL) are commonly used therapies for elderly and/or comorbid patients. No head-to-head comparison has been carried out. Within the Italian campus CLL network, we performed a retrospective study on CLL patients without TP53 disruption treated with IB or G-CHL as first-line therapy. Patients in the G-CHL arm had a higher CIRS score and the worst renal function. The overall response rates between the G-CHL and IB arms were similar, but more complete remissions (CRs) were achieved with G-CHL (p = 0.0029). After a median follow-up of 30 months, the progression-free survival (PFS, p = 0.0061) and time to next treatment (TTNT, p = 0.0043), but not overall survival (OS, p = 0.6642), were better with IB than with G-CHL. Similar results were found after propensity score matching and multivariate analysis. While PFS and TTNT were longer with IB than with G-CHL in IGHV unmutated patients (p = 0.0190 and 0.0137), they were superimposable for IGHV mutated patients (p = 0.1900 and 0.1380). In the G-CHL arm, the depth of response (79% vs. 68% vs. 38% for CR, PR and SD/PD; p < 0.0001) and measurable residual disease (MRD) influenced PFS (78% vs. 53% for undetectable MRD vs. detectable MRD, p = 0.0203). Hematological toxicities were common in the G-CHL arm, while IB was associated with higher costs. Although continuous IB provides better disease control in CLL, IGHV mutated patients and those achieving an undetectable MRD show a marked clinical and economic benefit from a fixed-duration obinutuzumab-based treatment.

EE12 A Probabilistic Cost-Effectiveness Analysis of Venetoclax and Obinutuzumab As a First-Line, 12-Month, Fixed Duration Therapy in Chronic Lymphocytic Leukemia (CLL) in Canada

To assess the cost effectiveness of venetoclax + obinutuzumab (VENCLAXTA® + GAZYVA®), (Ven+O) for the frontline treatment of CLL (1L CLL) in Canada from a publicly funded healthcare system perspective.

Guideline for the treatment of chronic lymphocytic leukaemia

Guideline for the treatment of chronic lymphocytic leukaemia

Evaluation of the frailty characteristics and clinical outcomes according to the new frailty-based outcome prediction model (Myeloma Risk Profile-MRP) in a UK real-world cohort of elderly newly diagnosed Myeloma patients.

The management of myeloma in the elderly is shifting its focus towards reducing the risk of under-treating fit patients and the risk of over-treating frail patients. Frailty assessment is required in this patient group in order to individualise treatment decisions. In addition to the proven prognostic values of the International Myeloma Working Group (IMWG) frailty score and the revised Myeloma Co-morbidity Index (R-MCI), a new easy-to-use frailty-based risk profile score (high-risk (i.e. frail), medium risk (i.e. intermediate-fitness) and low-risk (i.e. fit)) named Myeloma Risk Profile (MRP) was shown to be predictive of survival in the clinical trial setting. In this retrospective real-world study, we set out to evaluate the frailty characteristics and clinical outcomes according to the different MRP scoring algorithm categories (frail vs. intermediate vs fit), in a high risk cohort of elderly newly diagnosed myeloma patients treated with the fixed-duration triplet therapy VCD (bortezomib with cyclophosphamide and dexamethasone). Clinical outcomes included: reason for treatment discontinuation, overall response rate (ORR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs). Out of 100 patients, 62 were frail, 27 were intermediate and 11 were fit, according to MRP scores. To enable meaningful comparisons between comparable numbers, subgroups analyses for ORR, OS, PFS, and AEs focused on frail (n = 62) versus intermediate or fit (n = 38) patients. The proportion of patients in each subgroup who were able to complete the planned course of treatment was (frail: 43.5% vs. intermediate or fit: 55.3%). A higher proportion in the frail subgroup discontinued therapy due to progressive disease (19.4% vs. 2.6%). Discontinuation due to toxicity was comparable across subgroups (14.5% vs. 15.8%), ORR in the total cohort was 75%, and this was comparable between subgroups (frail: 74.2% vs. intermediate or fit: 76.3%). There was a trend for a shorter median OS in the frail subgroup but without a statistical significance: (frail vs. intermediate or fit): (46 months vs. not reached, HR: 1.94, 95% CI 0.89–4.2, p = 0.094). There was no difference in median PFS between subgroups: (frail vs. intermediate or fit): (11.8 vs. 9.9 months, HR: 0.99, 95% CI: 0.61–1.61, P = 0.982). This cohort demonstrated a higher incidence rate of AEs in frail patients compared to those in the intermediate or fit group: patients with at least one any grade toxicity (85.5% vs. 71.1%), patients with at least one ≥G3 AE (37.1% vs. 21.1%). In conclusion, our study is to the first to evaluate clinical outcomes according to MRP in a high risk real-world cohort of patients treated exclusively with the proteasome inhibitor-based VCD therapy. Our study demonstrated a trend for worse OS in addition to worse AE outcomes in the frail group, but no difference in PFS with this fixed-duration therapy. MRP is an easy-to-use tool in clinical practice; its prognostic value was validated in the real-world in a large cohort of patients from the Danish Registry. Further evaluation of MRP in the real-world when continuous therapies are used, can further support the generalisability of its prognostic value in elderly myeloma patients.

Treatment paradigm in Waldenström macroglobulinemia: frontline therapy and beyond.

Waldenström macroglobulinemia (WM) is an indolent lymphoplasmacytic lymphoma. Recent strides made in the genomic profiling of patients with WM have led to the identification of many novel therapeutic targets. Patients with WM can present with asymptomatic disease and not all patients require treatment. When criteria for initiating systemic therapy are met, the choice of therapy depends on the tumor genotype (MYD88 and CXCR4 mutation status), patient preference (fixed versus continuous duration therapy, oral versus intravenous route, cost), associated medical comorbidities, and adverse effect profile of the treatment. In the absence of head-to-head comparison between chemoimmunotherapy and Bruton’s tyrosine kinase inhibitors in otherwise fit patients with a MYD88L265P mutation, our preference is fixed duration therapy with four to six cycles of chemoimmunotherapy with bendamustine–rituximab. In this review, we discuss the role of MYD88 and CXCR4 mutation in treatment selection, and current data for frontline and salvage treatment options in patients with WM.

Treatment strategies for a rapidly evolving landscape in chronic lymphocytic leukemia management.

With the advent of targeted therapies for chronic lymphocytic leukemia (CLL), treatment choice has expanded and patients are living longer. Careful consideration is needed regarding treatment duration and sequence, how best to meet patients' needs, balancing toxicities while improving long-term survival and maximizing depth of response. This review addresses these considerations and discusses current targeted treatment dilemmas. Targeted therapies have dramatically transformed the CLL treatment landscape. Two treatment paradigms have emerged using B-cell lymphoma 2 inhibitors (BCL2i) and Bruton's tyrosine kinase (BTK): (i) fixed duration and (ii) continuous treatment. The BCL2i venetoclax can attain deep remissions with a fixed-duration approach, resulting in high rates of undetectable minimal residual disease (uMRD) in treatment-naïve and relapsed/refractory (R/R) patients with CLL. BTKis such as ibrutinib and acalabrutinib achieve high objective response rates and long-term disease control, although they rarely attain complete response or uMRD status as monotherapy. Numerous studies are evaluating the clinical utility of BTKi and BCL2i as combination therapies, where deep remissions have been found to occur. MRD status may also be a useful marker for deciding when to stop continuous therapy, and randomized trials on MRD-guided treatment strategies are currently ongoing. The current treatment choice between continuous or fixed-duration therapy should be based on comorbidities, risks, preferences, and treatment goals, whilst areas of emerging clinical interest include the potential utility of BTKi-BCL2i combination therapies, as well as an MRD-guided treatment strategies in the future.

Fixed Duration Combination Therapy with Ibrutinib (ibr) and Venetoclax (ven) Leads to Deep Responses in Relapsed/Refractory (rel/ref) Chronic Lymphocytic Leukemia (CLL): Results of a Phase 2 Study

Fixed Duration Combination Therapy with Ibrutinib (ibr) and Venetoclax (ven) Leads to Deep Responses in Relapsed/Refractory (rel/ref) Chronic Lymphocytic Leukemia (CLL): Results of a Phase 2 Study

Phase II Study of Acalabrutinib and High-Frequency Low-Dose Subcutaneous Rituximab in Patients with Previously Untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Background: Continuous Bruton's tyrosine kinase (BTK) inhibition represents an effective and easily administered oral therapy for patients with CLL; however, it is not curative, can have serious side effects, and is expensive. Novel combinations may provide deep remissions allowing fixed duration therapy. The second generation BTK inhibitor acalabrutinib (ACALA) has demonstrated an improved safety profile compared to ibrutinib. Importantly, unlike ibrutinib, ACALA does not inhibit anti-CD20 monoclonal antibody dependent cellular phagocytosis (VanDerMeid et al, Cancer Immuno Res 2018). Using standard doses, rituximab (RTX) rapidly exhausts the finite innate immune system cytotoxic capacity (Pinney, et al Blood 2020) and also causes loss of cell membrane CD20 from CLL cells by trogocytosis. Previous studies have shown that high frequency low dose (HFLD) IV RTX (20mg/m 2 three times per week) was effective and limited loss of CD20 (Zent, et al Am J Hematol, 2014). Subcutaneous (SQ) RTX is FDA approved in CLL, has similar efficacy and pharmacokinetics, and can be self-administered. This phase II study tested the efficacy and tolerability of the combination of ACALA and HFLD RTX as initial treatment for patients with treatment-naïve CLL.Methods: Eligible patients were treated with 50mg RTX on day 1 and 3 of each week for six 28-day cycles. The first dose was administered IV over 2 hours. If tolerated, subsequent doses were SQ and could be self-administered at home by trained patients. ACALA 100mg BID therapy was initiated on cycle 1 day 8 for a minimum of 12 cycles. Treatment response was assessed during cycles 12 and 24. Patients achieving an iwCLL complete response (CR) with undetectable minimal residual disease (uMRD) by 6-color flow cytometry (£ 1:10 -4)at either time point could stop therapy. The primary objective was to determine the rate of iwCLL CR with a secondary endpoint of rate of uMRD.Results: 37 patients have been treated with a median follow-up of 14 months. Baseline demographics were male/female (22/15) and median age 67 years (range 40-78). High-risk genetic features included TP53 mutation (21.6%), del17p (13.5%), del 11q (16.2%), unmutated IGHV (62.2%), NOTCH1 mutation (21.6%) and SF3B1 mutation (10.8%).Grade 3/4 AEs occurring in ≥5% of patients were infections (13.5%), neutropenia (8.1%) and anemia (8.1%). No patients discontinued therapy due to AEs and there were no deaths on treatment. The most common (≥20%) AEs (all grades and all causality) were infusion-related reactions (62.1%), infections (56.8%) (upper respiratory infections in 29.7% of patients, urinary tract infections in 18.9%, COVID-19 pneumonia in 8.1%), fatigue (51.3%), anemia (51.3%), headache (43.2%), rash or other skin changes (32.4%), thrombocytopenia (29.7%), bruising (27.0%), and diarrhea (21.6%). Injection site reactions (8.1%) from SQ RTX were grade 1. Three patients contracted COVID-19 while on study during times of high community transmission prior to the availability of vaccines. Two required hospitalization, one contracted the virus following cycle 1 requiring a delay in RTX, and all patients remained on ACALA while COVID-19 positive.27 patients have completed 12 cycles and been evaluated for response. All patients responded with 1 MRD+ CR, 20 partial responses (PR), and 6 PR with sustained lymphocytosis. 10 of these patients have completed 24 cycles and had a sustained PR. One patient with del17p and TP53 mutation had progressive disease after 25 cycles of therapy. All other patients remain on treatment per protocol.Conclusion: HFLD RTX and ACALA is a tolerable, effective and convenient therapy that could be the basis for regimens incorporating other novel agents. It is notable that three patients have contracted COVID-19 during the trial; however, none required intubation, and all remained on ACALA during their infection. This at-home combination markedly decreased patient infection risk during the COVID-19 pandemic. This regimen has the potential to enable RTX to be administered at facilities with limited medical IV infusion capacity which could be very useful in rural and economically disadvantaged areas. While all patients have responded to therapy, no patients to date have achieved an uMRD CR, suggesting that additional agents are required to allow for time-limited treatment. DisclosuresBaran: AstraZeneca/Acerta: Research Funding. Friedberg: Novartis: Other: DSMC ; Acerta: Other: DSMC ; Bayer: Other: DSMC . Reagan: Kite, a Gilead Company: Consultancy; Genentech: Research Funding; Seagen: Research Funding; Curis: Consultancy. Casulo: Verastem: Research Funding; Genentech: Research Funding; BMS: Research Funding; Gilead: Research Funding. Zent: TG Therapeutics: Research Funding; Acerta/AstraZeneca: Research Funding. Barr: Morphosys: Consultancy; Janssen: Consultancy; Bristol Meyers Squibb: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy; TG Therapeutics: Consultancy; Beigene: Consultancy; Seattle Genetics: Consultancy; Abbvie/Pharmacyclics: Consultancy; Gilead: Consultancy.