Depth Of Treatment Response Research Articles

Real-World Patterns of MRD Testing and Impact on Treatment for Chronic Lymphocytic Leukemia Patients

INTRODUCTION Therapeutic options for Chronic Lymphocytic Leukemia (CLL) have advanced significantly over time, resulting in a heterogeneous treatment landscape. Insights into the depth of treatment response can be gained through highly-sensitive detection of residual cancer cells using measurable (also known as minimal) residual disease (MRD) testing. Initially, MRD testing was limited to prognostic use within clinical trials. However, in recent years it has expanded into various clinical settings, although the extent of real-world use is not well established. METHODS 766 individuals with CLL enrolled in the Leukemia and Lymphoma Society (LLS) registry had their medical records collected and data extracted via the Invitae Ciitizen® platform, a patient-centric platform that leverages HIPAA right-of-access to organize clinical data into a standardized, research-ready format, using a combination of machine learning and human clinician review. Proprietary logic-based algorithms were used to characterize lines of therapy (LOTs), MRD testing methods, outcomes and duration of therapy. Descriptive findings are reported below. RESULTS Of the 766 CLL participants, 117 (15%) received a total of 311 MRD tests (mean=3 tests/person, median=2, max=16). 67 individuals had one or more MRD negative results (134 negative results total) and 78 individuals had one or more MRD positive results (177 positive results total). 56/117 (47.9%) patients had one or more MRD tests as part of a clinical trial, for a total of 132/311 (42.2%) MRD tests performed during a trial. Total MRD tests included 260 (83.6%) evaluated by flow cytometry, 8 (2.6%) by next generation sequencing (NGS), with the remainder not having documented methods (43; 13.8%). Since 2014, when MRD testing was integrated as a prognostic indicator in clinical trials, there has been increasing use of MRD testing ( Figure 1) within this cohort, as assessed by percentage of individuals receiving one or more tests per year. Interestingly, there is a peak of percentage tested in a clinical trial setting in 2017, after which a continued increase in those tested outside of a clinical trial setting shifts the overall proportion down. We also note the appearance of NGS testing in 2018. The 117 individuals who were MRD tested received 40 unique LOTs (e.g., “obinutuzumab, venetoclax”). We then quantified the MRD outcomes as either “achieved MRD-negative” or “did not achieve MRD-negative” for the most commonly-used therapies (n≥5) ( Table 1). Ibrutinib and acalabrutinib monotherapies had the lowest proportion of MRD-negative outcomes (1/15 and 0/6, respectively), whereas obinutuzumab-venetoclax +/- ibrutinib combination therapies had the highest proportion of MRD-negative outcomes (4/5 and 17/17, respectively). In order to assess the impact of MRD outcome on treatment patterns, the duration of therapy following a MRD-positive and negative test were evaluated. Therapy continued a mean duration of 691 days (n=126, median=488) after a MRD-positive test and 419 days (n=66, median=230) after a MRD negative test. CONCLUSION In this real-world dataset of 766 individuals with CLL, we detect an increasing rate of MRD testing since 2014. Notably, this usage is not limited to the clinical trial setting, underscoring the growing significance of MRD testing as a more general tool for evaluating disease control. Exploration of which LOTs achieve proportionally more MRD-negative statuses highlights that venetoclax-containing fixed-duration regimens as well as venetoclax monotherapy have higher rates of MRD-negativity. Conversely, BTK monotherapies ibrutinib and acalabrutinib were associated with the lowest percentage of MRD-negative outcomes. Finally, we find that the duration of therapy from the time of MRD testing is shorter when the result is MRD-negative, suggesting that MRD testing as a component of outcomes assessment used in the real-world setting may be useful in deciding when to discontinue therapy. This aligns with ongoing clinical trials investigating fixed duration therapies and the use of MRD-negative status as an outcome measure to assess depth of remission. Future studies on larger datasets will explore how MRD testing is integrated into clinical practice and its impact on treatment decisions.

Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens.

Despite improving outcomes, 40% of patients with newly diagnosed multiple myeloma treated with regimens containing daratumumab, a CD38-targeted monoclonal antibody, progress prematurely. By integrating tumor whole-genome and microenvironment single-cell RNA sequencing from upfront phase 2 trials using carfilzomib, lenalidomide and dexamethasone with daratumumab ( NCT03290950 ), we show how distinct genomic drivers including high APOBEC mutational activity, IKZF3 and RPL5 deletions and 8q gain affect clinical outcomes. Furthermore, evaluation of paired bone marrow profiles, taken before and after eight cycles of carfilzomib, lenalidomide and dexamethasone with daratumumab, shows that numbers of natural killer cells before treatment, high T cell receptor diversity before treatment, the disappearance of sustained immune activation (that is, B cells and T cells) and monocyte expansion over time are all predictive of sustained minimal residual disease negativity. Overall, this study provides strong evidence of a complex interplay between tumor cells and the immune microenvironment that is predictive of clinical outcome and depth of treatment response in patients with newly diagnosed multiple myeloma treated with highly effective combinations containing anti-CD38 antibodies.

The Clinical Significance of Oligoclonal Bands in Patient with Multiple Myeloma

To investigate the clinical value of oligoclonal bands (OB) in patients with multiple myeloma (MM). The laboratory test and clinical data of 624 newly diagnosed MM patients admitted to Blood Diseases Hospital of Chinese Academy of Medical Sciences from January 2013 to December 2019 were retrospectively analyzed, including 30 patients with OB, and the clinical characteristics, treatment effects and survival of OB and non-OB patients were analyzed and compared. OB occurred in 11.8% (22/187) of patients who received autologous stem cell transplantation(ASCT) and only 1.8% (8/437) of patients who did not receive ASCT (P=0.000). The median time to the appearance of oligoclonal bands was 3.2(0.6-10.5) months after transplantation. The M protein types of oligoclonal bands mainly include IgG κ, IgG λ, IgM λ and λ light chains. In the presence of oligoclonal bands, 90% of patients were evaluated as complete remission (CR) and above. There were no statistically significant differences in disease stage, tumor burden, and genetic abnormalities between OB and non-OB patients. Among the all patients, the prognosis of OB patients was significantly better than that of non-OB patients, and OB patients showed deeper disease remission (significantly higher CR rate, MRD negative rate, and longer MRD negative duration). Among patients who underwent ASCT, OB patients showed earlier immune recovery, but the depth of treatment response and survival outcomes were similar between OB and non-OB patients, it was no statistically difference. Although OB patients showed earlier immune reconstitution, this did not translate into better survival, suggesting that the better prognosis of OB patients was mainly related to deeper and durable remission rather than early immune reconstitution. Further analysis in patients who received ASCT and obtained MRD negative indicated that there was no additional survival benefit in patients with OB. The better prognosis of OB patients may be related to the deeper treatment response, but not to the early immune reconstitution. The appearance of OB is only a sign of deep remission and early immune reconstitution in patients, it cannot be translated into survival benefit of MM patients.

Total Diffusion Volume Estimated By Whole-Body Diffusion Magnetic Resonance Imaging for the Assessment of Tumor Burden in Multiple Myeloma

Introduction: Whole-body diffusion-weighted magnetic resonance imaging (wbDWI) is an emerging imaging technique for assessing the tumor burden of patients with multiple myeloma (MM). Total diffusion volume (tDV) is a potential parameter to quantify the tumor volume of bone marrow (BM) images obtained by wbDWI. The apparent diffusion coefficient (ADC) value, also calculated with wbDWI, has the potential to accurately evaluate the treatment response of MM; however, correlation between tDV and the treatment response of MM remains poorly studied. Methods: We retrospectively selected patients with newly-diagnosed, symptomatic MM who were treated at Kameda Medical Center, Japan, from January 2016 to November 2019; we analyzed the tDV obtained by wbDWI before and after treatment. We used the BD score software (PixSpace, Japan) to analyze tDV. Briefly, the regions of interest, including areas with abnormally high signal intensity of diffusion weighted imaging considered to contain myeloma lesions in the BM or extramedullary tissue, were automatically obtained with a b-value of 900 s/mm2. Physiological areas with high signal intensity were removed manually. Threshold values for distinguishing diseased areas from the background were manually adjusted to cover all bone lesions. Diagnosis and response were assessed using the International Myeloma Working Group criteria. We compared tDV before and after treatment, and in each response category. Comparison of continuous variables between the two categories and between three or more sets were analyzed using Wilcoxon test and Kruskal-Wallis test, respectively. All statistical analyses were performed using R (version 4.0.2; R Foundation, Vienna, Austria). Results: We analyzed 42 patients (18 men; median age, 71.5 years; interquartile range [IQR]: 65.0-77.0) whose pre- and post-treatment tDV values were available. The type of myeloma at diagnosis included immunoglobulin G (IgG) (n=21, 50%), immunoglobulin A (IgA) (n=12, 28%), and light chain alone (n=9, 21.4%). Three patients (7.1%) underwent wbDWI when they achieved partial response (PR); 6 patients (14.2%) achieved very good partial response (VGPR), 3 patients (7.1%) achieved complete response (CR), and 30 patients (71.4%) achieved stringent complete response (sCR). In all patients, median tDV decreased significantly before and after the treatment (median, 464.24 mL [IQR: 152.99-929.23] and 108.2 mL [IQR: 27.76-368.85], respectively; p<0.001) (Figure 1). Median tDV after treatment trended to be progressively low for patients who achieved PR, VGPR, CR, and sCR (tDV: 381.33 mL, 218.85 mL, 19.26 mL, and 63.97 mL, respectively; p=0.12). However, these values were not statistically significant. We also compared the tDV before and after treatment for patients who achieved less than CR (PR and VGPR) and those who achieved CR or better (≥CR). The median tDV of the patients who achieved less than CR was 298.24 mL [IQR: 147.88-381.33] and for those who achieved ≥CR was 62.65 mL [IQR: 19.26-279.79] (p=0.02) (Figure 2). We also compared the decreasing rate of tDV before and after treatment between patients who achieved less than CR and those who achieved ≥CR. The median decreasing rate of tDV was 61.0% 72.0% for patients who achieved less than CR and ≥CR, respectively. Although this result was not statistically significant, the data suggests that patients who achieved a deeper response tended to have a larger decreasing rate of tDV. Conclusions: Our data shows that tDV correlates with the depth of treatment response, and thus, is a potentially useful marker for evaluating the treatment response in patients with MM. Disclosures No relevant conflicts of interest to declare.

The (Neutrophils + Monocyte)/Lymphocyte Ratio Is an Independent Prognostic Factor for Progression-Free Survival in Newly Diagnosed Multiple Myeloma Patients Treated With BCD Regimen.

ObjectiveBortezomib is one of the important drugs that have made breakthrough progress in multiple myeloma (MM) in the past 10 years. However, the heterogeneity of its efficacy makes it difficult to predict the risk of disease progression. The purpose of this study is to determine the prognostic significance of the (neutrophils + monocytes)/lymphocytes ratio (NMLR) in newly diagnosed MM patients who received BCD regimen therapy in terms of progression-free survival (PFS).MethodsA total of 150 patients who fulfilled the International Myeloma Working Group (IMWG) criteria were enrolled in the study retrospectively. The prognostic value of NMLR was evaluated by 150 patients with MM who were treated with BCD (bortezomib + cyclophosphamide + dexamethasone) regimen therapy. NMLR was calculated by the ratio of (neutrophils + monocyte) to lymphocytes. According to receiver operating characteristic curves, the cutoff value was 1.90. The patients were divided into high NMLR group (H-NMLR, NMLR ≥1.90) and low NMLR group (L-NMLR, NMLR <1.90). The clinical characteristics, treatment responses and PFS of the two groups were analyzed.ResultsThe median age of the patients was 61 years. Fifty-five (36.67%) patients showed lower NMLR at initial diagnosis. Although NMLR was unable to discriminate prognosis in ISS stage I/II patients, interestingly, the addition of NMLR to the ISS further defined prognosis particularly in stage III. Low-NMLR group who achieved early immune reconstruction significantly higher than that of the high-NMLR group (P < 0.001). NMLR value was 1.98 ± 1.02 for the patients who achieved early immune reconstruction, which was 3.26 ± 2.52 for the patients without immune reconstruction (P < 0.05). Compared with the H-NMLR group, the levels of β2-microglobulin, serum creatinine and calcium were lower, and the very good partial response or better (≥VGPR) ratio was higher in L-NMLR group. The L-NMLR group experienced a superior median PFS compared with the H-NMLR group (24.0 versus 15.5 months; P < 0.001). In addition, several other prognostic factors of PFS were estimated, including the high-risk cytogenetics, β2-microglobulin and the depth of treatment response 3 months after treatment with BCD regimen. Moreover, NMLR was an independent predictor of PFS including non-high risk cytogenetics (0.587; P = 0.031).ConclusionIn patients with newly diagnosed MM undergoing BCD regimen, the NMLR <1.90 was an independent prognostic factor for PFS as well as early immune reconstruction and lower disease burden.

Abstract P6-01-02: Spatial heterogeneity of response on whole-body MRI to first line hormonal therapy predicts progression-free survival in metastatic breast cancer

Abstract Background Whole-body magnetic resonance imaging (WB-MRI) reliably identifies types of response to systemic therapy in metastatic breast cancer (MBC) through analysis of changes in water diffusivity, cellularity and cell variability. We adapted a novel methodology that uses WB-MRI to capture spatial response heterogeneity data via the METastasis Response Assessment Diagnostic System (MET-RADS). This study evaluates whether the extent of spatial heterogeneity seen at initial response assessment is predictive of progression-free survival (PFS) in patients on first line hormonal therapy for MBC. Methods Patients on first line hormonal therapy for MBC who had undergone baseline and on-treatment response assessment WB-MRI scans were identified. All scans were performed using a published WB-MRI protocol. Patients with disease progression at their first WB-MRI response assessment were excluded from further analysis. Criteria for response assessment utilised the methodology described by MET-RADS. A Likert five-point Response Assessment Category (RAC) score (1=response highly likely; 2=response likely; 3=no change; 4=progression likely; 5=progression highly likely) was applied separately to 14 defined anatomic regions. Within each region, two RAC scores were recorded to reflect both the dominant and the next most common pattern of response behaviour. Data were therefore captured on inter- and intra-regional response heterogeneity. A novel Response Heterogeneity Index (RHI) was calculated from the regional RAC scores. The RHI value summarised the overall response heterogeneity seen across all involved regions, with higher scores indicative of greater heterogeneity of response. Depth of overall response to treatment was defined as the mean RAC score for all involved regions, with lower scores indicative of a greater depth of treatment response. RHI and mean RAC score data were separated by median values into two groups for analysis. Results Thirty-three patients were suitable for analysis. Patients with higher levels of response heterogeneity (defined as RHI≥4; n=16) had significantly shorter PFS than those with RHI &amp;lt;4 (n=17; median PFS: 12 vs 24 months; log rank test p=0.006). Depth of initial response, as defined by mean RAC score, and PFS were unrelated (mean RAC ≤2.5 (n=17) vs mean RAC &amp;gt;2.5 (n=16); median PFS: 27 vs 23 months; log rank test p=0.699). There was no correlation between RHI score and mean RAC score (r2=0.002). Conclusions Lower variability of response behaviour at first treatment assessment is predictive of longer treatment duration in patients receiving first line hormonal therapy for MBC. The spatial heterogeneity of response evident on WB-MRI may represent the genetic heterogeneity and clonal evolution of MBC, which are key factors in the development of treatment resistance. Citation Format: Kosmin M, Makris A, Sokhi H, Thijssen T, Padhani A. Spatial heterogeneity of response on whole-body MRI to first line hormonal therapy predicts progression-free survival in metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-01-02.

Abstract P4-20-02: Value of cancer care for metastatic breast cancer patients and providers

Abstract Background: The landscape of treatment options and associated prognosis for patients with metastatic breast cancer (MBC) is rapidly evolving. In response to these advances in therapy, numerous organizations have invested considerable resources into developing evaluation frameworks seeking to clarify the value of new therapies. While some of these frameworks foster patient-provider shared decision making, others are more payer focused, and all are limited in their incorporation of patient perceptions of value and evidence on treatment aspects most meaningful to patients. Objectives: 1) To identify the attributes of treatment that patients with MBC value most, and 2) to explore the alignment between patient valuation of treatment attributes and healthcare provider perceptions of what patients value. METHODS: Four 90-minute focus groups were conducted: two with patients (aged &amp;lt;50 years and aged ≥50 years) and two with healthcare providers (oncologists and oncology nurses) who treat patients with MBC. Using semi-structured discussion guides tailored to each participant group, patient and provider perceptions of the factors most important to patients when considering treatment were explored as well as various sources of perceived value in cancer care. Discussions were audio recorded and transcribed. Thematic analysis identified attributes patients with MBC consider when making treatment decisions, and concordance between patients and healthcare providers was assessed. Results: A total of 24 patients and providers (n=5 patients &amp;lt;50 years, n=5 patients ≥50 years, n=7 oncologists, and n=7 nurses) participated in four different focus groups. The factors of greatest importance to patients included: impact of treatment side effects on daily life, depth of treatment response, longevity of life, and the value of hope in traversing their illness and achieving survival landmarks and goals. In contrast, oncologists focused predominantly on clinical considerations, such as treatment effectiveness and managing side effects. Oncology nurses noted similar clinical factors as oncologists, but also aligned more closely with patients on humanistic elements informing treatment decision-making. Conclusion: This analysis reveals that while patient and healthcare provider assessments of value in treating MBC are well-aligned with respect to clinical factors such as managing side effects and depth of treatment response; patients also prioritize emotional and psychological factors, -- like having hope and avoiding suffering -- in addition to clinical factors. Moving forward, patient-centered value frameworks for MBC will need to address this gap between what providers and payers value and patient goals and priorities. Citation Format: May SG, Chung AH, Vania DK, Hou N, MacEwan J, Batt K, Kurian AW, Zacker C, Globe D, Goldman DP. Value of cancer care for metastatic breast cancer patients and providers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-20-02.