Enhanced clinical assessment of hematologic malignancies through routine paired tumor and normal sequencing.

Genomic profiling of hematologic malignancies has augmented our understanding of variants that contribute to disease pathogenesis and supported development of prognostic models that inform disease management in the clinic. Tumor only sequencing assays are limited in their ability to identify definitive somatic variants, which can lead to ambiguity in clinical reporting and patient management. Here, we describe the MSK-IMPACT Heme cohort, a comprehensive data set of somatic alterations from paired tumor and normal DNA using a hybridization capture-based next generation sequencing platform. We highlight patterns of mutations, copy number alterations, and mutation signatures in a broad set of myeloid and lymphoid neoplasms. We also demonstrate the power of appropriate matching to make definitive somatic calls, including in patients who have undergone allogeneic stem cell transplant. We expect that this resource will further spur research into the pathobiology and clinical utility of clinical sequencing for patients with hematologic neoplasms.

Clonal Characterization and Somatic Hypermutation Assessment by Next-Generation Sequencing in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Detailed Description of the Technical Performance, Clinical Utility, and Platform Comparison.

Somatic hypermutation status of the IGHV gene is essential for treating patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Unlike the conventional low-throughput method, assessment of somatic hypermutation by next-generation sequencing (NGS) has potential for uniformity and scalability. However, it lacks standardization or guidelines for routine clinical use. We critically assessed the performance of an amplicon-based NGS assay across 458 samples. Using a validation cohort (35 samples), the comparison of two platforms (Ion Torrent versus Illumina) and two primer sets [leader versus framework region 1 (FR1)] in their ability to identify clonotypic IGHV rearrangement(s) revealed 97% concordance. The mutation rates were identical by both platforms when using the same primer set (FR1), whereas a slight overestimation bias (+0.326%) was found when comparing FR1 with leader primers. However, for nearly all patients this did not affect the stratification into mutated or unmutated categories, suggesting that use of FR1 may provide comparable results if leader sequencing is not available and allowing for a simpler NGS laboratory workflow. In routine clinical practice (423 samples), the productive rearrangement was successfully detected by either primer set (leader, 97.7%; FR1, 94.7%), and a combination of both in problematic cases reduced the failure rate to 1.2%. Higher sensitivity of the NGS-based analysis also detected a higher frequency of double IGHV rearrangements (19.1%) compared with traditional approaches.

Healthcare resource utilization and costs associated with first-line ibrutinib compared to chemoimmunotherapy treatment among Medicare beneficiaries with chronic lymphocytic leukemia.

OBJECTIVE: This retrospective observational study aimed to compare healthcare resource utilization and costs of Medicare beneficiaries with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who received ibrutinib versus chemoimmunotherapy (CIT) in first line (1 L). METHODS: Fee-for-service (FFS) and Medicare Advantage (MA) claims data were used to identify adults with a CLL/SLL diagnosis initiating 1 L ibrutinib single agent or CIT between 4 March 2016 and 30 September 2017 (index date). HRU and costs (Medicare spending) were evaluated during 1 L Oncology Care Model (1 L OCM) episodes (the first six months post-index) and over the observed 1 L duration. Patients' baseline characteristics were balanced using inverse probability of treatment weighting. Mean monthly cost differences (MMCDs) obtained from ordinary least square regressions were used to compare costs between ibrutinib and CIT cohorts. RESULTS: In the Medicare FFS dataset (ibrutinib: n = 2014; CIT: n = 2050), ibrutinib patients incurred significantly higher monthly pharmacy costs (1 L OCM: MMCD = $4878, p < .0001; 1 L duration: MMCD= $4892, p < .0001) that were fully offset by lower monthly medical costs (1 L OCM: MMCD= -$8289, p < .0001; 1 L duration: MMCD=-$5888, p < .0001), yielding a monthly total healthcare cost reduction (1 L OCM: MMCD=-$3411, p < .0001; 1 L duration: MMCD=-$996, p < .0001) relative to CIT patients. In the MA dataset (ibrutinib: n = 293; CIT: n = 303), ibrutinib was also associated with a monthly total healthcare cost reduction (1 L OCM: MMCD=-$10,459; 1 L duration: MMCD=-$5492). CONCLUSIONS: In Medicare patients with CLL/SLL, 1 L ibrutinib single agent was associated with total monthly cost savings relative to 1 L CIT, driven by lower monthly medical costs that fully offset higher monthly pharmacy costs.

Assessment of the Efficacy of Therapies Following Venetoclax Discontinuation in CLL Reveals BTK Inhibition as an Effective Strategy.

PURPOSE: Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood. EXPERIMENTAL DESIGN: To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies]. RESULTS: We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve (n = 130), and 81% were idelalisib naïve (n = 263). ORR to BTKi was 84% (n = 44) in BTKi-naïve patients versus 54% (n = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons. CONCLUSIONS: For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies.See related commentary by Rogers, p. 3501.

The evolving use of minimal residual disease (MRD) assessment in chronic lymphocytic leukemia.

The treatment of chronic lymphocytic leukemia (CLL) has changed remarkably throughout the past decade, with patients achieving deeper and more durable responses. Importantly, this clinical activity has been found to translate to prolonged survival. With some treatments, these responses are now allowing patients to stop therapy after 1 or 2 years, a concept referred to as "fixed duration." However, not all patients experience these outcomes. How to determine which patients can safely stop treatment remains unclear. Minimal residual disease (MRD) is emerging as a prognostic biomarker. In CLL, undetectable MRD has been shown to correlate with prolonged progression-free survival and, in some cases, overall survival. The incorporation of MRD status into clinical decision-making is not yet widely done, primarily based on the lack of prospective clinical trial data. As the endpoint of MRD status becomes more common in clinical trials of CLL, the role in the clinical setting will become more clear. Furthermore, prognostic models will help to determine the utility of MRD as a surrogate endpoint in clinical studies. This monograph examines clinical trial data regarding the role of MRD in CLL, and provides recommendations on how to incorporate MRD assessment into clinical management.

Comparison of Time to Next Treatment, Health Care Resource Utilization, and Costs in Patients with Chronic Lymphocytic Leukemia Initiated on Front-line Ibrutinib or Chemoimmunotherapy.

BACKGROUND: Studies assessing ibrutinib's economic burden versus chemoimmunotherapy (CIT) focused on pharmacy costs but not medical costs. This study compared time to next treatment (TTNT), health care resource utilization (HRU), and total direct costs among patients with chronic lymphocytic leukemia (CLL) initiating front-line ibrutinib single agent (Ibr) or CIT. MATERIALS AND METHODS: Optum Clinformatics Extended DataMart De-Identified Databases were used to identify adults with ≥ 2 claims with a CLL diagnosis initiating front-line Ibr or CIT from February 12, 2014 to June 30, 2017. Inverse probability of treatment weighting was used to control for potential differences in baseline characteristics between the Ibr and CIT cohorts. Two periods were considered: entire front-line therapy (until initiation of second-line therapy) and first 6 months of front-line therapy. Comparisons with a subgroup of CIT patients initiating bendamustine/rituximab (BR) were also conducted. RESULTS: TTNT was significantly longer for Ibr (N = 322) relative to CIT (N = 839; hazard ratio, 0.54; P = .0163; Kaplan-Meier rates [24 months]: Ibr = 88.6%, CIT = 75.9%) and the subset of CIT patients treated with BR (N = 455; hazard ratio, 0.54; P = .0208; Kaplan-Meier rates [24 months]: Ibr = 89.0%, BR = 79.0%). During the entire front-line therapy, Ibr patients had significantly fewer monthly days with outpatient visits (rate ratio = 0.75; P = .0200). Ibrutinib's higher pharmacy costs (mean monthly cost difference [MMCD] = $6,849; P < .0001) were offset by lower medical costs (MMCD = -$10,615; P < .0001), yielding net savings (MMCD = -$3,766; P < .0001) versus CIT. Ibr was associated with net savings (MMCD = -$5,569; P < .0001) versus BR. Cost savings and reductions in HRU were more pronounced during the first 6 months of front-line therapy. CONCLUSION: During front-line CLL treatment, Ibr was associated with longer TTNT, fewer monthly days with outpatient visits, and net monthly total cost reduction versus CIT and BR.

Adverse events, resource use, and economic burden associated with mantle cell lymphoma: a real-world assessment of privately insured patients in the United States.

In view of recent therapeutic advances in mantle cell lymphoma (MCL), the aim of this retrospective cohort analysis was to assess treatment patterns, adverse events (AEs), resource utilization, and health care costs in patients with MCL in a US-based commercial claims database. A total of 783 patients with MCL (median age = 65 years) were selected. Among patients receiving systemic therapy (n = 457), the most common treatment regimens were bendamustine/rituximab (BR) (41.1%), rituximab/cyclophosphamide/doxorubicin/vincristine (RCHOP) (26.7%), rituximab monotherapy (20.4%), and ibrutinib monotherapy (14.2%). Mean monthly costs during treatments with BR, RCHOP, rituximab, and ibrutinib were $12,958, $24,719, $13,153, and $21,690, respectively. Mean monthly cost during follow-up was $13,650 among patients with ≥6 AEs versus $5131 among those without AEs. The costs of MCL varied considerably by treatment regimen and care setting. The overall economic burden of managing patients with MCL can be substantially affected by costs associated with managing AEs occurring during treatment.

Drivers of treatment patterns in patients with chronic lymphocytic leukemia stopping ibrutinib or idelalisib therapies.

Novel therapies including kinase inhibitors (KI) have led to high and durable response in patients with chronic lymphocytic leukemia (CLL), however, some patients stop therapy. This study evaluates reasons for treatment changes among CLL patients who stopped KI in real-world practice. Sixty-nine US oncologists/hematologists provided patient-level data abstracted from charts of CLL adult patients who initiated a KI and later (1) switched to another anti-neoplastic regimen (Switched cohort), (2) discontinued the KI and remained untreated (Discontinued cohort), or (3) restarted the same KI after an interruption of ≥60 days (Restarted cohort). Demographics, clinical/treatment characteristics, and reasons for stopping, restarting, and switching the KI therapy were described. In the Switched cohort, reasons for stopping included disease progression (72.5%), low/no disease activity (3.9%), adverse event [AE]/ intolerance/comorbidity (15.7%), and planned cellular therapies (7.9%). In the Discontinued cohort, approximately half (46.0%) of patients stopped KI therapy because they were terminally ill/died, or were moved to best supportive care - these patients were older, had more severe disease, and high comorbidity burden. The other half (54.0% of patients) stopped due to low/no disease activity (24.0%), AEs/toxicity (12.0%), or patient-requested drug holiday (18.0%). In the Restarted cohort, the most common reasons for stopping KIs were patient request (37.3%), AEs/intolerance (31.4%), and economic reasons (10%). Patients restarted when disease progressed (60.8%) or when they recovered from the AE (33%). Reasons for KI stop and subsequent treatment patterns were varied and multifactorial, suggesting heterogeneous disease management and a need for more evidence around supporting strategies and physician education.