ALBERT

Description: Key Points The MD Anderson Symptom Inventory for CML can be used to collect patient-reported symptoms for research and clinical practice. Thirty percent of patients in chronic-phase CML and on TKIs experience moderate symptoms that interfere with daily functioning.

Description: The objective of this study was to prospectively assess the relationship between symptom severity and changes in inflammatory cytokines around the time of diagnosis of acute GVHD in AML/MDS patients during the first 100 days of allo-BMT. Methods: Weekly symptom assessment with the M. D. Anderson Symptom Inventory was done for 30 patients over time of BMT. A panel of inflammatory cytokines (IL-1ra, IL-6, IL-8, IL-10, IL-12, TNF-a) was assayed at multiple time points (pre BMT, conditioning, BMT day, Day 1, nadir, Day 7, 14, 21, 28, 60, 90–100, also including days 1, 3, 5, 10 and 15 after diagnosis of a GVHD for the 26 patients who developed it). Results: Of the 26 patients, 69% had grade 1 GVHD, 27% had grade 2, and 4% had grade 3. 42% were treated with 2mg/kg of steroids, 31% with topical steriods. Figure 1 displays Loess curves that show the multiple symptom pattern for the 26 GVHD patients. These nonspecific symptoms reached their highest levels before the day of diagnosis. Immediate symptom reduction after diagnosis was most likely caused by administration of steroids. The Lowess curves in Figure 2 show the changes in serum cytokines levels pre- and post-GVHD (log based 10). IL-8 was significantly correlated with some symptoms before and after GVHD (Table 1). Conclusion: During development of GVHD in the acute phase of allo-BMT, there is an observed relationship of certain symptom severity and increased or decreased inflammatory cytokine levels in this pilot study. Further study is warranted for a causal link between general sickness and specific cytokines during human GVHD development. Table 1. Correlations between symptoms severity and cytokines Levels before and after the Development of GVHD in the First 100 Days after Allo-BMT IL-8 Pre-GVHD Shortness of breath r = −0.708, P

Description: Background: Chronic, low-grade adverse events (AEs) are common in CML patients (pts) treated with the BCR-ABL1 tyrosine kinase inhibitor (TKI) imatinib (IM) and may decrease quality of life (Efficace, Blood. 2011;118:4554) and adherence to therapy (Marin, J Clin Oncol. 2010;28:2381). These AEs may result in dose modifications and contribute to suboptimal response. Alternative TKIs are available with the potential to reduce AEs, improve tolerability, and support long-term treatment goals. The second-generation TKI dasatinib (DAS) has demonstrated efficacy in pts previously treated with IM in the CA180-034 trial (Shah, Blood. 2014;123:2317). We present the analysis of CA180-400 (NCT01660906), an open-label, multicenter phase 4 study designed to determine if chronic, low-grade nonhematologic AEs in IM-treated pts improve after switching to DAS. Methods: Adult CML-CP pts who had not failed previous IM therapy (complete hematologic response by 3 mo, partial cytogenetic response [PCyR] by 6 mo, or complete cytogenetic response [CCyR] by 12 mo [Baccarani, Blood. 2013;122:872]) and had a chronic, grade 1/2 nonhematologic IM-related AE persisting for ≥2 mo or recurring ≥3 times in the prior 12 mo, despite best supportive care, were switched to DAS 100 mg once daily until disease progression, treatment failure, unacceptable AE, withdrawal of consent, or study discontinuation at 12 mo. The primary endpoint was the frequency of chronic, grade 1/2 nonhematologic IM-related AEs that decreased in grade or resolved within 3 mo following DAS initiation. Treatment-emergent DAS-related AEs and pt-reported symptom burden using MD Anderson Symptom Inventory (MDASI)-CML symptom severity and interference scores (0-10 scale; 10=worst) were also evaluated 3 mo following the switch to DAS. Results: Thirty-nine pts were enrolled in the trial. Median age was 57 y (range 23-81 y), with 31% ≥65 y. Median duration of prior IM was 47 mo and 49% had received

Description: Patients who undergo allogeneic BMT experience a rapid increase in multiple symptoms, including pain, fatigue, poor appetite, drowsiness, dry mouth, and disturbed sleep, from pre-BMT to nadir of white blood cell count. The objective of this study was to prospectively evaluate baseline levels of serum inflammatory cytokines and other factors related to symptom development from pre-BMT to nadir. Methods: Repeated multiple-symptom assessments with the M. D. Anderson Symptom Inventory (MDASI) were completed for 30 patients with AML/MDS at day of hospital admission (baseline), day of conditioning, day of BMT, day of nadir, and day 11 of BMT. A panel of serum inflammatory cytokines (IL-1ra, IL-6, IL-8, IL-10, IL-12, TNF-a) was assayed at baseline, conditioning, day of BMT, day after BMT, and at nadir. Results: Patients self reported multiple symptoms that peaked 3 days after nadir. We adjusted for potential confounding factors, including age, sex, race, disease status pre-BMT, infusion dose of CD34+, and conditioning regimen, that could have affected symptom outcomes in the mixed effect models for symptom severity. Race was the only significant factor affecting the severity of the baseline symptom cluster (pain, fatigue, poor appetite, disturbed sleep, drowsiness, and dry mouth) and the change in symptom severity from baseline to peak (P

Description: Background: Symptom burden is the impact of disease and treatment symptoms on daily functioning. The MD Anderson Symptom Inventory for chronic myeloid leukemia (MDASI-CML) is a brief valid and reliable measure of the severity of 20 symptoms common to patients with CML and symptom interference with 6 daily activities. Patients rate symptoms at their worst and interference in the last 24-hours on 0 to 10 scales (0=no symptom or interference; 10=as bad as can be imagined or complete interference). Aims: Our aim was to psychometrically define cut points for mild, moderate, and severe symptoms for the MDASI-CML based on the interference with daily activities from the symptoms reported by the patients. Methods: This study was a secondary analysis of combined data from patients who completed the MDASI-CML at least once on 3 clinical trials and one observational study. Rather than the usual mean score, a summed score of the 5 most severe symptoms (Top5) from one completed MDASI-CML for each patient was calculated. The possible range of Top5 scores was 0 (all 5 symptoms not present) to 50 (all 5 symptoms as bad as could be imagined). Patients reporting none of the Top5 symptoms (Top5 score = 0) were excluded from analysis. For the optimal cut points, a multivariate analysis of variance (MANOVA) was used to categorize the Top5 scores as mild (from 1 to the lower cut point), moderate (from the lower cut point to the upper cut point), and severe (from the upper cut point to 50). Top5 score was used as the independent variable and the mean score of the 6 interference items as the dependent variable. The largest F ratio from the MANOVA was used to determine optimal boundaries for the cut points. Results: MDASI-CML ratings from 394 patients were included. Current treatments were: imatinib = 74 patients, dasatinib = 146 patients, nilotinib = 114 patients, ponatinib = 37 patients, other tyrosine kinase inhibitors (TKIs) = 11 patients, drugs other than TKIs = 4 patients, and no treatment = 8 patients. Means and standard deviations of the Top5 symptoms are in Table 1. A graph of the relationship of the Top5 scores to the mean interference score is in Figure 1. Sixty-eight patients (17.5%) with Top5 score = 0 were excluded from the MANOVA analysis. The optimal cut point ranges (number reporting; percent) were mild 1-14 (213; 54.7), moderate 15-24 (64; 16.5), and severe 25-50 (44; 11.3). The F ratios for the optimal cut points were 22.58 (Wilks λ), 18.63 Pillai's Trace), and 26.76 (Hotelling Lawley Trace). Conclusion/Summary: MDASI-CML Top5 scores of less than 15 are mild symptoms that cause little interference with daily activities. Top5 scores of 15-24 indicate moderate symptoms with some impairment of daily functioning. Top5 scores of 25 of higher indicate severe symptoms with a significant impact on daily activities. Based on the impact on daily functioning, differences in patient status between levels of symptom severity (mild, moderate, severe) can be considered clinically meaningful. Patients with moderate to severe symptoms deserve further evaluation and active symptom management. Cut points for the MDASI-CML can be useful to clinicians in making treatment decisions and managing patients and in clinical trials to identify significant treatment related toxicities and differences. Table 1 Descriptive Statistics of 5 Most Severe MDASI-CML Symptoms (N=394) Table 1. Descriptive Statistics of 5 Most Severe MDASI-CML Symptoms (N=394) Figure 1 Relationship between the Sum of 5 Most Severe Symptoms and the Mean Interference Score Figure 1. Relationship between the Sum of 5 Most Severe Symptoms and the Mean Interference Score Disclosures No relevant conflicts of interest to declare.

Description: Abstract 1396 Poster Board I-418 Introduction: Hematopoietic stem cell transplantation (HSCT) is an intensive therapy that may cure or control a variety of hematological malignancies. Although the toxicities associated with HSCT are well-described, patient report of symptom burden is rarely addressed. Lack of understanding of symptoms may result in failure to address symptoms and return patients to optimum functioning. Differences in the pattern of symptom burden between autologous (auto) and allogeneic (allo) HSCT and the special needs for symptom management that each type of therapy may require has not been addressed. The purpose of this study was to compare the symptom burden of patients undergoing allo- and auto-HSCT. Patients and Methods: Retrospective analysis of a combined data set of 155 patients from 3 longitudinal studies exploring the symptom burden of HSCT. Patients used modified versions of the M. D. Anderson Symptom Inventory (MDASI) to rate the severity of their symptoms (13 items) and the degree to which their symptoms interfered with daily living (6 items) on a 0–10 scale. Patients completed the MDASI at baseline, during conditioning therapy, on day of transplant, twice weekly for 4 weeks, and 1 to 2 times weekly for another 10 weeks. Symptom burden was measured as the area under the curve (AUC) of the mean MDASI symptom severity from baseline to 14 weeks post-HSCT. Results: Average age of the allo-HSCT patients was 52.9 years, whereas the auto-HSCT patients averaged 53.2 years. The allo- and auto-HSCT patients were 57% and 69% male, respectively, and 73% and 82% Caucasian, respectively. All allo-HSCT patients were being treated for acute myelogenous leukemia/myelodyspalastic syndrome; 66% of the auto-HSCT patients had multiple myeloma and 26% had non-Hodgkin's lymphoma. All allo-HSCT patients received short-course methotrexate as part of their graft-versus-host disease (GVHD) prophylaxis. Symptom severity peaked during the Week 1 post-HSCT for the auto-HSCT patients and Week 2 for the allo-HSCT patients. Three of the most severe symptoms experienced by both groups were lack of appetite, fatigue, and physical weakness. Other most severe symptoms experienced by the auto-HSCT patients were feeling physically sick and nausea. The other most severe symptoms reported by the allo-HSCT patients were pain and difficulty sleeping. Figure 1 shows the symptom burden of the 7 most severe symptoms combined for the two groups. Peak symptom severity was highest for the auto-HSCT group, but the overall AUC and symptom burden was greater for the allo-HSCT group because they remained more symptomatic throughout the 14 weeks of the study, whereas the auto-HSCT patients had returned to baseline levels by the end of 8 weeks. Although sore mouth was not one of the most severe symptoms, the auto-HSCT patients reported significantly more sore mouth during Week 1 post-HSCT (p ≤ 0.002), whereas the allo-HSCT patients reported significantly more sore mouth the second week (p ≤ 0.001). During Week 2, pain severity was significantly greater for the allo-HSCT patients than for the auto-HSCT patients (p ≤ 0.001), while diarrhea was significantly more severe for the auto-HSCT patients than for the allo-HSCT patients (p ≤ 0.001). Conclusions: Although patients undergoing auto-HSCT experience more severe acute symptoms from the conditioning regimen, they return to baseline symptom levels several weeks after HSCT. Allo-HSCT patients experience a slightly later peak in symptoms, mostly likely due to the effects of GVHD methotrexate prophylaxis, and continue to experience increased symptom burden up to 3 months post-HSCT, likely due to the development of GVHD and infection complications. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4920 Background: Patients with multiple myeloma (MM) undergoing induction therapy experience both disease- and therapy-related symptoms. This longitudinal study investigated the association between the trajectory of symptom severity and changes in levels of inflammatory markers. Methods: Patients with MM repeatedly rated symptoms via the M. D. Anderson Symptom Inventory (MDASI) during induction therapy. Patients contributed serum samples before start of every cycle of chemotherapy. A panel of cytokines, including interleukin (IL)-6, soluble IL-6 receptor (sIL-6R), soluble IL-1 receptor type 1 (sIL-1R1), soluble tumor necrosis factor receptor type 2 (sTNF-R2), monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1 alpha (MIP-1A), and IL-10, was examined by Luminex method. Ordinal regression analyses were used to describe the interaction of cytokines and symptom outcomes across time, adjusted for patient and clinical factors of age, sex, diabetes diagnosis, anemia, body mass index, co-morbidities, tumor stage, Eastern Cooperative Oncology Group performance status (ECOG PS), prior treatment status, tumor response, opioid use, and chemotherapy regimen. Results: Sixty-two patients were enrolled on study; of these, 89% received bortezomib-based induction therapy. During induction, the most severe patient-reported symptoms were (in order of severity): fatigue, muscle weakness, disturbed sleep, pain, drowsiness, bone aches, and numbness. Fatigue was persistently the most severe symptom, while therapy-induced neuropathy (MDASI numbness item) increased significantly from baseline (P=.01). We observed significant longitudinal associations between sIL-1R1 and distress and sadness (both P=.02); between sIL-6R and disturbed sleep (P=.001), poor appetite (P=.04), and sore mouth (P=.006); between IL-6 and pain, fatigue, nausea, and sore mouth (all P

Description: Abstract 2573 Introduction: The United States Food and Drug Administration (FDA) recognizes patient-reported outcomes (PROs) as acceptable measures of treatment benefit and risk in medical product clinical trials. The FDA requires that patient input be included in the development and testing of PRO instruments. We have adopted a three-step process for the development of multi-symptom PROs that includes patient input in each step. This method is being used for the development of the M. D. Anderson Symptom Inventory (MDASI) for Philadelphia-chromosome-positive chronic myeloid leukemia (CML). The MDASI is a PRO measure of symptom burden, defined as the combined impact of all disease-related and therapy-related symptoms on one's ability to function as one did before the onset of disease or therapy, in patients with cancer. The core MDASI includes 13 symptom severity items and 6 interference items rated at their worst in the last 24 hours on a 0–10 scale, with 0 meaning no symptom or interference and 10 meaning as bad as can be imagined or complete interference. Patients and Methods: The first step in the process was qualitative interviews with 35 patients with CML about their symptom experiences. Symptoms were extracted by descriptive exploratory analysis from interview transcripts. Step 2 was grading of the relevance of the symptoms (0 to 4 scale) from Step 1 by an expert panel that included professional care providers as well as patients with CML and their family caregivers. Symptoms that received a mean relevance rating of ≥ 3 were added to the 13 symptom items and 6 interference items of the core MDASI for validation in Step 3. One hundred and sixty patients with CML are completing the experimental MDASI-CML, which will undergo psychometric validation and item reduction. The first 30 patients in Step 3 completed a cognitive debriefing interview about their experience of completing the MDASI-CML. Results: Patient characteristics are in Table 1. No personal information was collected on the expert panel members. Thirty-nine symptoms (13 core and 26 CML-specific) were extracted from the Step 1 qualitative interviews and rated by the expert panel. Four physicians, 5 nurses, 3 patients, and 3 family caregivers returned ratings. Six of the 26 CML-specific items had mean relevance ratings of ≥ 3. The experimental MDASI-CML includes the 13 core symptoms, 6 CML-specific symptoms, and 6 core interference items (Table 2). During the cognitive debriefing, over 80% of patients reported that the MDASI-CML items were not at all difficult to complete or understand, were completely comfortable to answer, and were not repetitive, and that the 0–10 scoring system for rating severity of symptoms and interference with daily activities was very easy to use. Nine patients listed 12 additional symptoms that should be included, but each symptom was only mentioned by 1 patient and had already been eliminated because of low relevance ratings by the expert panel. Conclusions: Inclusion of patient input at each step of PRO development ensures that the instrument measures what is important to patients and enhances content validity. It further ensures that the measure is easy to understand and complete. Psychometric validation of the MDASI-CML is proceeding. Disclosure: No relevant conflicts of interest to declare.