Le‐Rademacher, Jennifer

Background/aims The goal of this article is to illustrate the utility of multi-state models in cancer clinical trials. Our specific aims are to describe multi-state models and how they differ from standard survival methods, to illustrate how multi-state models can facilitate deeper understanding of the treatment effect on multiple paths along the disease process that patients could experience in cancer clinical trials, to explain the differences between multi-state models and time-dependent Cox models, and to briefly describe available software to conduct such analyses. Methods Data from 717 newly diagnosed acute myeloid leukemia patients who enrolled in the CALGB 10603 trial were used as an illustrative example. The current probability-in-state was estimated using the Aalen–Johansen estimator. The restricted mean time in state was calculated as the area under the probability-in-state curves. Cox-type regression was used to evaluate the effect of midostaurin on the various clinical paths. Simulation was conducted using a newly constructed shiny application. All analyses were performed using the R software. Results Multi-state model analyses of CALGB 10603 suggested that the overall improvement in survival with midostaurin seen in the primary analysis possibly resulted from a higher complete remission rate in combination with a lower risk of relapse and of death after complete remission in patients treated with midostaurin. Simulation results, in a three-state illness-death without recovery model, demonstrate that multi-state models and time-dependent Cox models evaluate treatment effects from different frameworks. Conclusion Multi-state models allow detailed evaluation of treatment effects in complex clinical trial settings where patients can experience multiple paths between study enrollment and the final outcome. Multi-state models can be used as a complementary tool to standard survival analyses to provide deeper insights to the effects of treatment in trial settings with complex disease process.

123 Background: Lymph node dissection, axillary or sentinel, often results in restrictions of arm movement, including range of motion (ROM), either temporarily or permanently. The objective of this secondary analysis was to determine if a lymphedema (LE) prevention program would also impact ROM in both the affected arm as well as the unaffected arm. Methods: As part of the Lymphedema Education and Prevention study (CALGB 70305), women from participating sites (N=41) were randomized to either the “education only” (n=253) arm (information about LE signs and symptoms and risk reduction strategies) or “education + exercise” (n=315) arm (education plus arm stretching and breathing exercises and a visit with a physical therapist). Self-administered surveys asking for how high the patient can reach with each arm at pre-surgery, 12 and 18 months after surgery were used to assess self-reports of ROM for each arm (5 categories in total: very little, about half, nearly full, overhead, and full). Differences in ROM between study groups for each arm were compared using chi-square tests before surgery, and 12 and 18 months after surgery. Results: Before surgery, women in the “education + exercise” group were less likely to report full ROM for both arms (left: 58% vs 75%; right: 57% vs 76%; p=0.0004 for both arms) compared to women in the “education only” group, while at 12 months, women in the “education + exercise” group reported greater ROM (left: 91% vs 84% p=0.16; right: 90% vs 83%; p=0.02) compared to women in the “education only” group. By 18 months, both groups approached 93% with full ROM for both arms. Conclusions: Women who participated in a LE prevention intervention that included exercise and a visit to a physical therapist regained full ROM in both arms sooner than women who did not receive the exercise intervention. All women receiving lymph node dissection should receive physical therapy to regain ROM quickly after surgery and to help maintain physical functioning. Support: UG1CA189823, UG1CA189817, UG1CA189819, U10CA180790, U10CA180836, U10CA180850, and UL1TR001409; Clinical trial information: NCT00376597.

BACKGROUND A nocebo is an inert substance associated with adverse events. Although previous studies have examined the positive (placebo) effects of such inert substances, few have examined negative (nocebo) adverse event profiles, particularly in older patients who have higher morbidity and can experience frequent and severe adverse events from cancer therapy. METHODS This study focused on placebo/nocebo‐exposed patients who participated in 2 double‐blind, placebo‐controlled, cancer therapeutic studies, namely, North Central Cancer Therapy Group trial NCCTG 97‐24‐51 and American College of Surgeons Oncology Group trial Z9001, with the goal of reporting the comparative, age‐based adverse event rates, as reported during the conduct of these trials. RESULTS Among the 446 patients who received only placebo/nocebo and who were the focus of the current report, 161 were aged ≥65 years at the time of respective trial entry, and 5234 adverse events occurred. Unadjusted adverse event rates did not differ significantly between patients aged ≥65 years and younger patients (rate ratio, 1.01; 99% confidence interval, 0.47‐2.02), and the findings were similar findings for grade 2 or worse adverse events and for all symptom‐driven adverse events (for example, pain, loss of appetite, anxiety). Adjustment for sex, ethnicity, baseline performance score, and individual trial resulted in no significant age‐based differences in adverse event rates. Similar findings were observed with an age threshold of 70 years. CONCLUSIONS Adverse events are equally common in older and younger cancer patients who are exposed to nocebo and thus require the same degree of clinical consideration regardless of age. Cancer 2017;123:4193–4198. © 2017 American Cancer Society .

Key Points Pembrolizumab was first shown to be clinically active in CLL patients with RT. PD-1 and PD-L1 expression in tumor microenvironment are promising biomarkers to select RT patients for PD-1 blockade.

104 Background: Lymphedema (LE), a side effect of BC treatment, affects 8%–56% of women. The study tested the effectiveness of an education only vs education + exercise intervention on LE incidence in a group randomized trial (NCT00376597) of 38 cooperative group sites. Methods: Newly diagnosed women with stage I-III BC were consented and arm circumference and range of motion were measured pre-surgery. After surgery, patients (pts) were enrolled based on the randomization assignment of their treating institution, stratified by their type of node dissection (sentinel or axillary), and received either: education only: its causes, signs, symptoms and risk reduction strategies, or education + personalized exercise instruction from a physical therapist, with elastic compression garments to wear during heavy arm use and air travel. Pts completed surveys and arm measurements at baseline (BL), 12 and 18 months with the LE endpoint defined as ≥ 10% difference in limb volume at any time from BL to 18 months or physician diagnosis of LE. Cochran-Mantel-Haenszel (CMH) tests were used to compare the LE-free rate between arms, adjusted for type of biopsy. Logistic regression assessed predictors of LE. Results: 568 pts were enrolled, 45% in education only, and 55% in education + exercise, with 554 (98%) included in the analyses. Pts were on average 57.7 years, White (83%), non-Hispanic (92%) and married (62%). 47% only had sentinel node dissection, 35% had mastectomy, and 37% had chemotherapy. The LE-free rate was 58% in education only vs 55% in education + exercise (CMH p = 0.73). Predictors of LE included surgery type (lumpectomy vs mastectomy, OR = 2.22, p < 0.001) and chemotherapy (no vs yes, OR = 1.73, p = 0.02), after adjusting for BMI and type of node dissection. Only one-third wore the sleeve at least 75% of the time and only 50% did LE exercises at least weekly. Conclusions: There was no difference by intervention arm in LE incidence by 18 months. Poor adherence in the education + exercise arm may have been a factor. Additional analyses will assess quality of life, body image and knowledge about LE by arm. Further research is needed to effectively prevent LE in pts after BC surgery. Research Support: UL1TR001409; U10CA037447, UG1CA189823 Clinical trial information: NCT00376597.

BACKGROUNDAutologous stem cell transplantation (SCT) is a common management strategy for select patients with immunoglobulin light‐chain amyloidosis, but no trials have documented improved overall survival.METHODSEighty‐nine patients with biopsy‐proven immunoglobulin light‐chain amyloidosis were allowed to select treatment with melphalan plus dexamethasone (n = 34) or SCT (n = 55); all patients were transplant eligible. Treatment preference resulted in imbalanced study arms. Patients who selected SCT were younger, more frequently had an Eastern Cooperative Oncology Group performance status score less than 2, had lower‐stage amyloidosis, and had a lower incidence of cardiac amyloidosis.RESULTSPatients receiving melphalan plus dexamethasone had a 3‐year progression‐free survival rate of 29.1% and an overall survival rate of 58.8%. Patients undergoing SCT had a 3‐year progression‐free survival rate of 51.7% and an overall survival rate of 83.6%. An attempt to match patients between the 2 arms in terms of risk produced 24 matched triplet sets (2 SCT patients for each melphalan‐dexamethasone patient); there was no difference in hematologic response, but there was better survival after autologous SCT. A propensity score–matched analysis of the cohorts (melphalan plus dexamethasone vs SCT) showed an overall mortality hazard ratio of 2.56 (P < .01).CONCLUSIONSAlthough the study had limitations, similar hematologic responses and improved survival were observed after SCT versus melphalan plus dexamethasone. Cancer 2016;122:2197–205. © 2016 American Cancer Society.

Purpose To analyze outcomes of hematopoietic cell transplantation (HCT) in T-cell non-Hodgkin lymphoma. Patients and Methods Outcomes of 241 patients (112 anaplastic large-cell lymphoma, 102 peripheral T-cell lymphoma not otherwise specified, 27 angioimmunoblastic T-cell lymphoma) undergoing autologous HCT (autoHCT; n = 115; median age, 43 years) or allogeneic HCT (alloHCT; n = 126; median age, 38 years) were analyzed. Primary outcomes were nonrelapse mortality (NRM), relapse/progression, progression-free survival (PFS), and overall survival (OS). Patient, disease, and HCT-related variables were analyzed in multivariate Cox proportional hazard models to determine association with outcomes. Results AutoHCT recipients were more likely in first complete remission (CR1; 35% v 14%; P = .001) and with chemotherapy-sensitive disease (86% v 60%; P < .001), anaplastic large-cell histology (53% v 40%; P = .04), and two or fewer lines of prior therapy (65% v 44%; P < .001) compared with alloHCT recipients. Three-year PFS and OS of autoHCT recipients beyond CR1 were 42% and 53%, respectively. Among alloHCT recipients who received transplantations beyond CR1, 31% remained progression-free at 3 years, despite being more heavily pretreated and with more refractory disease. NRM was 3.5-fold higher (95% CI, 1.80 to 6.99; P < .001) for alloHCT. In multivariate analysis, chemotherapy sensitivity (hazard ratio [HR], 1.8; 95% CI, 1.16 to 2.87) and two or fewer lines of pretransplantation therapy (HR, 5.02; 95% CI, 2.15 to 11.72) were prognostic of survival. Conclusion These data describe the roles of autoHCT and alloHCT in T-cell non-Hodgkin lymphoma and suggest greater effectiveness earlier in the disease course, and limited utility in multiply relapsed disease. Notably, autoHCT at relapse may be a potential option for select patients, particularly those with anaplastic large-cell lymphoma histology.

Abstract The best conditioning regimen before allogeneic transplantation for high-risk diffuse large B-cell lymphoma (DLBCL) remains to be clarified. We analyzed data from 396 recipients of allotransplants for DLBCL receiving myeloablative (MAC; n = 165), reduced intensity (RIC; n = 143), or nonmyeloablative conditioning (NMAC; n = 88) regimens. Acute and chronic GVHD rates were similar across the groups. Five-year nonrelapse mortality (NRM) was higher in MAC than RIC and NMAC (56% vs 47% vs 36%; P = .007). Five-year relapse/progression was lower in MAC than in RIC/NMAC (26% vs 38% vs 40%; P = .031). Five-year progression-free survival (15%-25%) and overall survival (18%-26%) did not differ significantly between the cohorts. In multivariate analysis, NMAC and more recent transplant year were associated with lower NRM, whereas a lower Karnofsky performance score (< 90), prior relapse resistant to therapy, and use of unrelated donors were associated with higher NRM. NMAC transplants, no prior use of rituximab, and prior relapse resistant to therapy were associated with a greater risk of relapse/progression. In conclusion, allotransplantation with RIC or NMAC induces long-term progression-free survival in selected DLBCL patients with a lower risk of NRM but with higher risk of lymphoma progression or relapse.